U.S. patent application number 13/957470 was filed with the patent office on 2014-02-06 for substituted amino-pyrimidine derivatives.
This patent application is currently assigned to Endo Pharmaceuticals Inc.. The applicant listed for this patent is Endo Pharmaceuticals Inc.. Invention is credited to Mallesham Bejugam, Subramanya Hoshalli, Srinivas Nanduri, Roger Astbury Smith, Aranapakam Venkatesan.
Application Number | 20140038952 13/957470 |
Document ID | / |
Family ID | 48980360 |
Filed Date | 2014-02-06 |
United States Patent
Application |
20140038952 |
Kind Code |
A1 |
Smith; Roger Astbury ; et
al. |
February 6, 2014 |
Substituted Amino-Pyrimidine Derivatives
Abstract
The present application provides novel substituted quinazoline
and pyrido-pyrimidine compounds and pharmaceutically acceptable
salts, prodrugs, and solvates thereof. Also provided are methods
for preparing these compounds. These compounds are useful in
co-regulating PI3K and/or mTOR activity by administering a
therapeutically effective amount of one or more of the compounds to
a patient. By doing so, these compounds are effective in treating
conditions associated with the dysregulation of the PI3K/AKT/mTOR
pathway. Advantageously, these compounds perform as dual PI3K/mTOR
inhibitors. A variety of conditions can be treated using these
compounds and include diseases which are characterized by
inflammation or abnormal cellular proliferation. In one embodiment,
the disease is cancer.
Inventors: |
Smith; Roger Astbury;
(Chester Springs, PA) ; Venkatesan; Aranapakam;
(Chadds Ford, PA) ; Bejugam; Mallesham; (Parbhani,
IN) ; Hoshalli; Subramanya; (Bangalore, IN) ;
Nanduri; Srinivas; (Hyderabad, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Endo Pharmaceuticals Inc. |
Malvern |
PA |
US |
|
|
Assignee: |
Endo Pharmaceuticals Inc.
Malvern
PA
|
Family ID: |
48980360 |
Appl. No.: |
13/957470 |
Filed: |
August 2, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61678694 |
Aug 2, 2012 |
|
|
|
Current U.S.
Class: |
514/230.5 ;
514/232.5; 514/234.2; 514/234.5; 544/105; 544/117; 544/119 |
Current CPC
Class: |
A61P 29/00 20180101;
C07D 239/94 20130101; C07D 403/14 20130101; C07D 409/14 20130101;
A61P 35/00 20180101; C07D 401/14 20130101; C07D 471/04
20130101 |
Class at
Publication: |
514/230.5 ;
544/119; 514/234.5; 544/117; 514/234.2; 514/232.5; 544/105 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 401/14 20060101 C07D401/14; C07D 403/14 20060101
C07D403/14; C07D 239/94 20060101 C07D239/94; C07D 409/14 20060101
C07D409/14 |
Claims
1. A compound of formula (I): ##STR00251## wherein: R.sup.1 is
optionally substituted aryl, optionally substituted heterocycle,
optionally substituted heteroaryl, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted alkylamino, optionally substituted
dialkylamino, optionally substituted arylamino, optionally
substituted heteroarylamino, optionally substituted
heterocycleamino, optionally substituted alkylcarbonylamino,
optionally substituted alkylsulfonylamino, optionally substituted
alkylthio, optionally substituted alkylsulfonyl, optionally
substituted alkoxy, optionally substituted aryloxy, optionally
substituted heteroaryloxy, optionally substituted heterocycleoxy,
optionally substituted alkylaminocarbonyl, optionally substituted
arylaminocarbonyl, optionally substituted heteroarylaminocarbonyl,
or optionally substituted heterocycleaminocarbonyl; R.sup.2 is
optionally substituted morpholine or thiomorpholine; R.sup.3 is H,
F, Cl, CH.sub.3, or CH.sub.3O; X is CH or N; or a pharmaceutically
acceptable salt, solvate, or prodrug thereof.
2. The compound according to claim 1, wherein R.sup.2 is
morpholine.
3. The compound according to claim 1, wherein R.sup.1 is a
substituted phenyl of the structure: ##STR00252## wherein: n is 1
to 5; each R.sup.8 is independently selected from the group
consisting of halogen, alkyl, aryl, alkylsulfonyl, alkylthio,
alkylcarbonylamino, halogenated alkylcarbonylamino,
alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl,
alkylaminocarbonylamino, alkylaminoalkylcarbonylamino,
hydroxyalkylcarbonylamino, heteroarylcarbonylamino,
heteroarylalkylcarbonylamino, heteroarylcarbonyl,
heterocyclecarbonylamino, arylcarbonylamino,
alkylsulfonylheterocyclecarbonyl, heterocyclecarbonyl,
heterocycleaminocarbonyl, heteroarylalkylamino, hydroxyalkylamino,
heterocyclealkylcarbonylamino, or cyanoalkylcarbonylamino.
4. The compound according to claim 1, wherein R.sup.1 is a
heteroaryl of the formula: ##STR00253## wherein: Z.sup.1 is O, S,
or NR.sup.5; Z.sup.2 is CR.sup.4 or N; R.sup.4H, alkyl,
C(O)(optionally substituted heterocycle), or C(O)NH(optionally
substituted heteroaryl); R.sup.5 is absent, H or alkyl; and p is 0
to 2.
5. The compound according to claim 1, wherein R.sup.1 is a
heteroaryl selected from the group consisting of: ##STR00254##
wherein: m is 0 to 4; q is 0 to 3; each R.sup.6 is, independently,
selected from the group consisting of halogen, piperidinyl,
4-CH.sub.3-piperidinyl, alkylsulfonyl, aminosulfonylalkyl, and
alkylcarbonylamino.
6. The compound according to claim 1, wherein R.sup.1 is an
optionally substituted benzo[b]oxazine.
7. The compound according to claim 1, wherein R.sup.1 is optionally
substituted alkyl.
8. The compound according to claim 7, wherein R.sup.1 is:
##STR00255## wherein: Y and Y' are, independently, N or CH; and
R.sup.7 is H, C(O)(hydroxyalkyl), C(O)(alkyl), or
NHC(O)(alkyl).
9. The compound according to claim 1, which is of formulae (II),
(III), or (IV): ##STR00256##
10. The compound according to claim 1 which is selected from the
group consisting of:
5-(7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-a-
mine;
5-(6-fluoro-7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl-
)pyrimidin-2-amine;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-acetamide;
4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-c-
yclopropyl-benzamide;
(5-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)fur-
an-2-yl)(4-methylpiperazin-1-yl)methanone;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)phenyl)-2-hyd-
roxy-2-methylpropanamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)cyclopropanecarboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-4-fluorobenzenesulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-2-(4-hydroxypiperidin-1-yl)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
phenyl)morpholine-4-carboxamide;
1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)m-
ethyl)piperazin-1-yl)-2-hydroxypropan-1-one;
5-(4-morpholino-7-(pyrimidin-5-yl)quinazolin-2-yl)pyrimidin-2-amine;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)phenyl)acetam-
ide;
5-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinoquinazolin-2-yl)pyrimidin-
-2-amine;
1-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)phen-
yl)-3-methylurea;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)phenyl)methan-
e-sulfonamide;
5-(4-morpholino-7-(thiophen-3-yl)quinazolin-2-yl)pyrimidin-2-amine;
5-(7-(5-(methylsulfonyl)pyridin-3-yl)-4-morpholinoquinazolin-2-yl)pyrimid-
in-2-amine;
5-(7-(2-fluoropyridin-3-yl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-amine-
;
5-(7-(3-(methylsulfonyl)phenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)-
pyrimidin-2-amine;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-methanesulfonamide;
5-(7-(1-methyl-1H-pyrazol-4-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)p-
yrimidin-2-amine;
5-(4-morpholino-7-(pyrimidin-5-yl)pyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-
-amine;
5-(7-(2-fluoropyridin-3-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-y-
l)pyrimidin-2-amine;
5-(7-(furan-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-ami-
ne
5-(7-(5-methylfuran-2-yl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrim-
idin-2-amine;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-N-methylacetamide;
1-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-3-methylurea;
1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-3-methylurea;
N-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
yridin-3-yl)acetamide;
N-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
yridin-3-yl)cyclopropanecarboxamide;
N-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
3-fluorophenyl)cyclopropanecarboxamide;
4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-m-
ethylbenzamide;
5-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-(-
pyridin-3-yl)furan-2-carboxamide;
1-(4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-y-
l)benzoyl)-piperazin-1-yl)ethanone;
(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phe-
nyl)(4-(methylsulfonyl)piperazin-1-yl)methanone;
4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-(-
thiazol-2-yl)benzamide;
4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-(-
pyridin-4-yl)benzamide;
(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phe-
nyl)(4-hydroxypiperidin-1-yl)methanone;
(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phe-
nyl)(4-hydroxypiperidin-1-yl)methanone;
3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N,N-
-dimethylbenzamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)phenyl)-2-(di-
methylamino)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)phenyl)-2-hyd-
roxy-propanamide;
(S)--N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)phenyl)--
2-hydroxy-propanamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-2-hydroxypropanamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-2-(dimethylamino)acetamide;
(S)--N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-
-yl)phenyl)-2-hydroxypropanamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-2-hydroxy-2-methylpropanamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-2-cyano-2-methylpropanamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-2-hydroxyacetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-2-fluoropropanamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
2-fluorophenyl)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-2-cyanoacetamide;
N-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
4-fluorophenyl)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
2-methylphenyl)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)cyclopentanecarboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)nicotinamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-5-methylfuran-2-carboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)cyclohexanecarboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-1-cyanocyclopropanecarboxamide;
N-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)cyclopropanecarboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)tetrahydro-2H-pyran-4-carboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)pyrazine-2-carboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)adamantane-1-carboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-4-methylpentanamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)furan-2-carboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-4-(trifluoromethyl)nicotinamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-1,2,3-thiadiazole-4-carboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-4-hydroxycyclohexanecarboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
4-fluoro-phenyl)nicotinamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
4-fluorophenyl)-5-methylfuran-2-carboxamide;
N-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-5-methylfuran-2-carboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-4-fluorobenzamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-3-methyl-1H-pyrazole-5-carboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)cyclobutanecarboxamide;
N-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)nicotinamide;
N-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)cyclobutanecarboxamide;
N-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)furan-2-carboxamide;
N-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-3-methyl-1H-pyrazole-5-carboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)cyclopropanesulfonamide;
N-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)cyclopropanesulfonamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-2-(4-methylpiperazin-1-yl)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-2-morpholinoacetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
4-fluorophenyl)-2-(4-methylpiperazin-1-yl)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
2-fluoro-phenyl)-2-(4-methylpiperazin-1-yl)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)phenyl)-4-met-
hyl-piperazine-1-carboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)phenyl)morpho-
line-4-carboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-4-methylpiperazine-1-carboxamide;
1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)methyl)pipera-
zin-1-yl)-2-hydroxypropan-1-one;
1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)methyl)pipera-
zin-1-yl)-2-hydroxy-2-methylpropan-1-one;
1-(4-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)methyl)pipera-
zin-1-yl)-ethanone;
N-(1-(2-(2-aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)methyl)piperi-
din-4-yl)-acetamide;
5-(4-morpholino-7-(piperazin-1-ylmethyl)pyrido[3,2-d]pyrimidin-2-yl)pyrim-
idin-2-amine;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
4-fluorophenyl)cyclopropanecarboxamide;
N-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
yridin-3-yl)methanesulfonamide;
3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-(-
3-fluoropyridin-4-yl)benzamide;
3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-c-
yclopropylbenzamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)p-
henyl)-5-fluoronicotinamide;
5-(7-(5-(4-methylpiperazin-1-yl)pyridin-3-yl)-4-morpholinopyrido[3,2-d]py-
rimidin-2-yl)pyrimidin-2-amine;
5-(7-(3-(4-methylpiperazin-1-yl)phenyl)-4-morpholinopyrido[3,2-d]pyrimidi-
n-2-yl)-pyrimidin-2-amine;
3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-(-
2-(dimethylamino)ethyl)benzamide;
3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-m-
ethylbenzamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
phenyl)propionamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
phenyl)isobutyramide;
5-(4-morpholino-7-(3-(piperazin-1-yl)phenyl)pyrido[3,2-d]pyrimidin-2-yl)p-
yrimidin-2-amine;
3-(4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-y-
l)-phenyl)piperazin-1-yl)-2,2-dimethyl-3-oxopropanenitrile;
1-(4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-y-
l)-phenyl)piperazin-1-yl)-2-hydroxy-2-methylpropan-1-one;
2-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
phenyl)propan-2-ol;
(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phe-
nyl)(4-methylpiperazin-1-yl)methanone;
6-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-2H--
benzo[b][1,4]oxazin-3(4H)-one;
1-(4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-y-
l)-phenyl)piperazin-1-yl)-2-(dimethylamino)ethanone;
2-(4-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-y-
l)-phenyl)piperazin-1-yl)ethanol;
N-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
2-(4-methylpiperazin-1-yl)phenyl)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
2-fluorophenyl)cyclopropanecarboxamide;
(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phe-
nyl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone;
N-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
2-(4-methylpiperazin-1-yl)phenyl)cyclopropanecarboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
phenyl)pivalamide;
N-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
2-fluorophenyl)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
2,4-difluorophenyl)acetamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
4-fluorophenyl)-1-cyanocyclopropanecarboxamide;
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
2-fluorophenyl)-1-cyanocyclopropanecarboxamide; and
N-(5-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
2-fluoro-phenyl)cyclopropanecarboxamide.
11. The compound according to claim 1 which is a prodrug of formula
(I).
12. The compound according to claim 11, wherein the prodrug is a
diester.
13. The compound according to claim 12, wherein the diester is
C(O))(C.sub.1 to C.sub.6 alkyl)OC(O)(C.sub.1 to C.sub.1 alkyl).
14. The compound according to claim 1, which is selected from the
group consisting of:
1-((acetyl(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidi-
n-7-yl)-phenyl)carbamoyl)oxy)ethyl acetate;
((acetyl(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin--
7-yl)-phenyl)carbamoyl)oxy)methyl acetate; and
(((3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
phenyl)(cyclopropanecarbonyl)carbamoyl)oxy)methyl acetate.
15. A method for co-regulating PI3K and mTOR, said method
comprising administering a therapeutically effective amount of a
compound of claim 1 to a patient in need thereof.
16. A method for treating a condition treatable by inhibiting the
PI3K/AKT/pathway, said method comprising administering a
therapeutically effective amount of a compound of claim 1 to a
patient in need thereof.
17. A method for treating a disease characterized by an abnormal
cellular proliferation resulting from a dysregulated PI3K/AKT/mTOR
pathway, said method comprising administering of a therapeutically
effective amount of a compound of claim 1 to a patient in need
thereof.
18. The method according to claim 17, wherein said disease is
cancer.
19. The method according to claim 17, wherein said condition is an
inflammatory disorder.
20. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
Description
BACKGROUND
[0001] With the onset of cancers which are refractory to most
conventional treatments, there is a need for new and effective
chemotherapeutics. As details emerge about the molecular etiology
of various cancers, new chemotherapeutics can be designed which
affect one or more vulnerable targets associated with a given
cancer at a sub-cellular level.
[0002] Certain cancers (and indeed other diseases of abnormal
cellular growth) include those which are due to the dysregulation
of one particular molecular signaling pathway in the body.
Restoring regulation of that particular pathway to normal or
near-normal levels can have a positive impact in treating the
patient, including a reduction in tumor size or even putting the
patient into remission.
[0003] For example, perturbations of the phosphoinositide 3-kinase
(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway
are closely associated with the etiology of most solid tumors. The
PI3K/AKT/mTOR pathway can be overactivated by a number of molecular
effectors, including chemokines, the loss of inositol
polyphosphate-4-phosphatase type II (INPP4B) or phosphatase and
tensin homolog (PTEN) expression, or by mutations in PI3K itself.
Overactivation of this pathway can manifest in a number of
molecular and morphological changes which are characteristic of
tumorigenesis, including increased cell proliferation, survival and
motility, and altered cell cycle entry. mTOR is a central regulator
of cell growth which acts by controlling cellular protein
translation. Several small molecules have been described as being
mTOR inhibitors which are useful for treating cancers. PI3K is a
heterodimeric enzyme that generates lipid second messengers, such
as phosphatidylinositol-3,4,5-triphosphate (PIP3), that mediate
signal transduction. PI3K enzymes regulate key signal transduction
pathways controlling vital cell processes that are implicated in
carcinogenesis, and include four isoforms; i.e., p110.alpha.,
p110.beta., p110.delta. and p110.gamma.. Specific mutations in
p110.alpha. have been identified in various cancers. Several small
molecules have been described as inhibitors of PI3K. Further, there
are a number of compounds, including wortmannins and rapamycins,
which have been shown to be highly potent and specific inhibitors
of PI3K and mTOR, respectively.
[0004] Indeed, several recent compounds have been described as
being useful in regulating the PI3K/mTOR pathway. For example,
GDC-0941, PX-866, XL-147, BKM-120, and BAY 80-6946 are inhibitors
of PI3K, whereas rapamycin, temsirolimus (CCI-779), everolimius
(RAD001), deforolimus (AP23573), OSI-027 and AZD8055 are inhibitors
of mTOR. However, intervention at a single point in a the
PI3K/AKT/mTOR signaling pathway may not be as effective in treating
solid tumors as targeting multiple pathway members. Administering
multiple drugs to a cancer patient, each of which inhibit a certain
target in the PI3K or mTOR pathway, carries its own risks in terms
of increased drug load, potential toxicity, drug-drug interactions
and the like. What remains in the art, therefore, is the need for
single compounds which regulate the PI3K/AKT/mTOR pathway by
targeting both PI3K and mTOR. Certain compounds recently described
in the art, including BEZ-235, XL-765, GSK-2126458, PKI-587
(PF-05212384), PF-04691502, and GDC-0980 have been reported to
target both PI3K and mTOR. However, the need remains for compounds
with this type of dual activity profile to be developed and
approved for clinical use.
SUMMARY OF THE INVENTION
[0005] In one aspect, the present invention provides a compound of
formula (I), wherein R.sup.1-R.sup.3 and X are defined herein, or a
pharmaceutically acceptable salt, prodrug or solvate thereof.
##STR00001##
[0006] In another aspect, compounds of formulae (II)-(IV) are
provided, wherein R.sup.1 and X are defined herein.
##STR00002##
[0007] In yet another aspect, the invention provides a
pharmaceutical composition comprising a compound of formulae (I) to
(IV), or a pharmaceutically acceptable salt, prodrug or solvate
thereof, and a pharmaceutically acceptable carrier.
[0008] In another aspect, methods for co-regulating PI3K and mTOR
are provided and include administering a therapeutically effective
amount of a compound described herein to a patient in need thereof.
Desirably, co-regulation includes inhibition of the PI3K/AKT/mTOR
pathway.
[0009] In still a further aspect, methods for treating a disease
characterized by abnormal cellular growth resulting from a
dysregulated PI3K/AKT/mTOR pathway are provided. These methods
include administering a therapeutically effective amount of a
compound described herein to a patient in need thereof. In one
embodiment, the disease is cancer. In another embodiment, the
disease is characterized by the presence of at least one solid
tumor. In yet another embodiment, the disease is characterized by
inflammation.
[0010] Other aspects and advantages of the invention will be
readily apparent from the following detailed description of the
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0011] The present invention provides novel compounds which have
capabilities in modulating two (2) members of the PI3K/AKT/mTOR
pathway, i.e., PI3K and mTOR. These compounds are can be used to
treat disease affected by a dysregulation of the PI3K/AKT/mTOR
pathway.
[0012] In the present invention, the compound is of formula (I), or
a pharmaceutically acceptable salt, prodrug or solvate thereof.
##STR00003##
[0013] In this structure, R.sup.1 is optionally substituted aryl,
optionally substituted heterocycle, optionally substituted
heteroaryl, optionally substituted alkyl, optionally substituted
alkenyl, optionally substituted alkynyl, optionally substituted
alkylamino, optionally substituted dialkylamino, optionally
substituted arylamino, optionally substituted heteroarylamino,
optionally substituted heterocycleamino, optionally substituted
alkylcarbonylamino, optionally substituted alkylsulfonylamino,
optionally substituted alkylthio, optionally substituted
alkylsulfonyl, optionally substituted alkoxy, optionally
substituted aryloxy, optionally substituted heteroaryloxy,
optionally substituted heterocycleoxy, optionally substituted
alkylaminocarbonyl, optionally substituted arylaminocarbonyl,
optionally substituted heteroarylaminocarbonyl, or optionally
substituted heterocycleaminocarbonyl.
[0014] In one aspect, R.sup.1 is optionally substituted phenyl. In
one embodiment, R.sup.1 is a substituted phenyl of the following
structure, wherein n is 1 to 5 and each R.sup.8 is independently
selected from among halogen, alkyl, aryl, alkylsulfonyl, alkylthio,
alkylcarbonylamino, halogenated alkylcarbonylamino,
alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl,
alkylaminocarbonylamino, alkylaminoalkylcarbonylamino,
hydroxyalkylcarbonylamino, heteroarylcarbonylamino,
heteroarylalkylcarbonylamino, heteroarylcarbonyl,
heterocyclecarbonylamino, arylcarbonylamino,
alkylsulfonylheterocyclecarbonyl, heterocyclecarbonyl,
heterocycleaminocarbonyl, heteroarylalkylamino, hydroxyalkylamino,
heterocyclealkylcarbonylamino, or cyanoalkylcarbonylamino. In a
further embodiment, the substituted phenyl is 3- or 4-substituted.
In yet another embodiment, R.sup.8 in the substituted phenyl is
selected from among F, CH.sub.3, C(CH.sub.3).sub.2OH,
NHC(O)CH.sub.3, NHC(O)CH.sub.2CH.sub.3NHC(O)CH(CH.sub.3).sub.2,
NHC(O)C(CH.sub.3).sub.3, NHC(O)CH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
N(CH.sub.3)C(O)CH.sub.3, NHC(O)NHCH.sub.3, NHSO.sub.2CH.sub.3,
NHC(O)CH.sub.2N(CH.sub.3).sub.2, NHC(O)C(CH.sub.3).sub.2OH,
NHC(O)CH(CH.sub.3)OH, NHC(O)CH.sub.2OH, NHC(O)CH(CH.sub.3)F,
NHC(O)C(CH.sub.3).sub.2CN, NHC(O)CH.sub.2CN, NHC(O)(cyclopropyl
optionally substituted with CN), NHC(O)cyclobutyl,
NHC(O)(cyclopentyl), NHC(O)(cyclohexyl optionally substituted with
OH), NHC(O)(adamantanyl), NHC(O)(pyridinyl), NHC(O)(furanyl
optionally substituted with CH.sub.3), NHC(O)(tetrahydropyranyl),
NHC(O)(pyrazinyl optionally substituted with CH.sub.3),
NHC(O)(piperazinyl optionally substituted with CH.sub.3),
C(O)(4-C(O)CH.sub.3-piperazinyl), NHC(O)CH.sub.2(piperazinyl
optionally substituted with CH.sub.3),
C(O)(4-SO.sub.2CH.sub.3-piperazinyl), C(O)NHCH.sub.3,
C(O)NHCH.sub.2CH.sub.2N(CH.sub.3).sub.2, C(O)N(CH.sub.3).sub.2,
C(O)NH(thiazolyl), C(O)NH(pyridinyl optionally substituted with
halogen), C(O)(piperidinyl optionally substituted with
CH.sub.2CH.sub.2OH, OH or CH.sub.3), NHC(O)(pyridinyl optionally
substituted with F or CF.sub.3), NHC(O)(thiadiazolyl),
C(O)NH(cyclopropyl), NHC(O)(phenyl optionally substituted with F),
NHSO.sub.2-(phenyl optionally substituted with F),
NHC(O)CH.sub.2(morpholinyl), NHC(O)CH.sub.2(piperidinyl optionally
substituted with OH), NHC(O)(morpholinyl), NHSO.sub.2(cyclopropyl),
piperidinyl optionally substituted with C(O)C(CH.sub.3).sub.2CN,
C(O)CH.sub.2N(CH.sub.3).sub.2, CH.sub.2CH.sub.2OH, or
C(O)C(CH.sub.3).sub.2OH, and SO.sub.2CH.sub.3.
##STR00004##
In another aspect, R.sup.1 is optionally substituted heteroaryl. In
one embodiment, R.sup.1 is a heteroaryl substituted with 0 to 3
R.sup.4 groups independently selected from among alkyl,
SO.sub.2(alkyl), alkylsulfonylamino, halogen, alkylcarbonylamino,
alkylcarbonylheterocyclecarbonyl, heterocyclecarbonyl, and
heteroarylaminocarbonyl. In a further embodiment, R.sup.1 is a
heteroaryl of the following structure, wherein Z.sup.1 is O, S, or
NR.sup.5; Z.sup.2 is CR.sup.4 or N; R.sup.4 is H, alkyl,
C(O)(optionally substituted heterocycle), or C(O)NH(optionally
substituted heteroaryl); R.sup.5 is absent, H or alkyl; and p is 0
to 2.
##STR00005##
In another embodiment, R.sup.1 is a substituted heteroaryl selected
from the group consisting of pyrazole, thiophene and furan. In
still a further embodiment, R.sup.1 is a heteroaryl substituted
with CH.sub.3, C(O)(optionally substituted heterocycle), or
C(O)NH(optionally substituted heteroaryl). In yet another
embodiment, R.sup.1 is a heteroaryl selected from among the
following structures, wherein m is 0 to 4; q is 0 to 3; and each
R.sup.6 is, independently, selected from among halogen,
piperidinyl, 4-CH.sub.3-piperidinyl, alkylsulfonyl,
aminosulfonylalkyl, and alkylcarbonylamino. In a further
embodiment, R.sup.1 is selected from among pyridine and pyrimidine.
In still another embodiment, R.sup.1 is substituted with F, Cl,
4-CH.sub.3-piperidinyl, NHCOCH.sub.3, NHC(O)(cyclopropyl), or
SO.sub.2CH.sub.3. In yet a further embodiment, R.sup.1 is an
optionally substituted benzo[b]oxazine. In another embodiment,
R.sup.1 is an optionally substituted benzo[b][1,3]oxazine or
benzo[b][1,4]oxazine. In still a further embodiment, R.sup.1 is a
benzo[b]oxazinone. In yet another embodiment, R.sup.1 is an
optionally substituted benzo[b][1,3]oxazin-2-one,
benzo[b][1,3]oxazin-4-one, benzo[b][1,4]oxazin-2-one, or
benzo[b][1,4]oxazin-3-one.
##STR00006##
[0015] In another aspect, R.sup.1 is an optionally substituted
heterocycle.
[0016] In still a further aspect, R.sup.1 is optionally substituted
alkyl. In one embodiment, R.sup.1 is CH.sub.2-(optionally
substituted heterocycle). In a further embodiment, R.sup.1 is
CH.sub.2-- (optionally substituted piperazinyl) or CH.sub.2--
(optionally substituted piperidinyl). In another embodiment,
R.sup.1 has the following structure, wherein Y and Y' are,
independently, N or CH; and R.sup.7 is H, C(O)(hydroxyalkyl),
C(O)(alkyl), or NHC(O)(alkyl). In still a further embodiment,
R.sup.1 has the following structure, wherein Y and Y' are,
independently, N or CH; and R.sup.7 is H, C(O)CH(CH.sub.3)OH,
C(O)C(CH.sub.3).sub.2OH, C(O)CH.sub.3, or NHC(O)CH.sub.3.
##STR00007##
[0017] In formula (I), R.sup.2 is optionally substituted morpholine
or thiomorpholine. In one embodiment, R.sup.2 is morpholine. In
another embodiment, R.sup.2 is morpholine substituted by one or
more methyl groups. In a further embodiment, R.sup.2 is
##STR00008##
[0018] Also in formula (I), R.sup.3 is H, F, Cl, CH.sub.3, or
CH.sub.3O and X is CH or N;
[0019] In one embodiment, the compound is of formula (I) or a
pharmaceutically salt, prodrug or solvate thereof. In this
structure, R.sup.1 is optionally substituted aryl, optionally
substituted heterocycle, optionally substituted heteroaryl, or
optionally substituted alkyl; R.sup.2 is optionally substituted
morpholine or thiomorpholine; R.sup.3 is H, F, Cl, CH.sub.3, or
CH.sub.3O; and X is CH or N.
##STR00009##
[0020] In another embodiment, the compound is of formula (I) or a
pharmaceutically salt, prodrug or solvate thereof. In this
structure, R.sup.1 is optionally substituted aryl, optionally
substituted heterocycle, optionally substituted heteroaryl, or
optionally substituted alkyl; R.sup.2 is optionally substituted
morpholine or thiomorpholine; R.sup.3 is H, F, Cl, CH.sub.3, or
CH.sub.3O; and X is CH or N.
##STR00010##
[0021] In still a further embodiment, the compound is of formula
(II) or a pharmaceutically salt, prodrug or solvate thereof,
wherein R.sup.1 and X are defined above.
##STR00011##
[0022] In another embodiment, the compound is of formula (III) or a
pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein R.sup.1 is defined herein.
##STR00012##
[0023] In a further embodiment, the compound is of formula (IV), or
a pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein R.sup.1 is defined herein.
##STR00013##
[0024] In yet another embodiment, the compound is of formula (I-A),
or a pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein R.sup.1 and R.sup.3 are defined herein.
##STR00014##
[0025] In still a further embodiment, the compound is of formula
(I-B), or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein R.sup.1 is defined herein.
##STR00015##
[0026] In another embodiment, the compound is of formula (I-C), or
a pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein R.sup.1 and R.sup.3 are defined herein.
##STR00016##
[0027] In yet a further embodiment, the compound is of formula
(I-D), or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein R.sup.1 and R.sup.3 are defined herein.
##STR00017##
[0028] In another embodiment, the compound is of formula (I-E), or
a pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein R.sup.2, R.sup.3, R.sup.8, and R.sup.9 are defined
herein.
##STR00018##
[0029] In still a further embodiment, the compound is of formula
(I-F), or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein R.sup.2, R.sup.3, R.sup.8, and R.sup.9 are defined
herein.
##STR00019##
[0030] In yet another embodiment, the compound is of formula (I-G),
or a pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein R.sup.3, R.sup.8, and R.sup.9 are defined herein.
##STR00020##
[0031] In still a further embodiment, the compound is of formula
(I-H), or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein R.sup.3, R.sup.8, and R.sup.9 are defined
herein.
##STR00021##
[0032] In another embodiment, the compound is of formula (I-J), or
a pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein R.sup.3, R.sup.8, and R.sup.9 are defined herein.
##STR00022##
[0033] In a further embodiment, the compound is of formula (I-K),
or a pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein R.sup.2 and X are defined herein.
##STR00023##
[0034] In still another embodiment, the compound is of formula
(I-L), or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein R.sup.2 and X are defined herein.
##STR00024##
[0035] In yet a further embodiment, the compound is of formula
(I-M), or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein R.sup.2 and X are defined herein.
##STR00025##
[0036] In still another embodiment, the compound is of formula
(I-N), or a pharmaceutically acceptable salt, prodrug or solvate
thereof, wherein R.sup.2 and X are defined herein.
##STR00026##
[0037] In a further embodiment, the compound is of formula (I-O),
or a pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein R.sup.2, R.sup.3, R.sup.7, X, and Y are defined herein.
##STR00027##
[0038] In another embodiment, the compound is of formula (I-P), or
a pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein R.sup.3, R.sup.7, X, and Y are defined herein.
##STR00028##
[0039] Representative "pharmaceutically acceptable salts" include
but are not limited to water-soluble and water-insoluble salts. In
one embodiment, the salt is of an acid or base. In another
embodiment, the salt is of an acid. In a further embodiment, the
salt is of an acid selected from among acetic, propionic, lactic,
citric, tartaric, succinic, fumaric, maleic, malonic, mandelic,
malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric,
sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic,
toluenesulfonic, trifluoroacetic, and camphorsulfonic. Optionally,
a composition of the invention may contain both a pharmaceutically
acceptable salt and the base form of a compound of the
invention.
[0040] In a further embodiment, a compound of the invention may be
a solvate. As used herein, a solvate does not significantly alter
the physiological activity or toxicity of the compounds, and as
such may function as pharmacological equivalents to non-solvate
compounds of the invention. The term "solvate" as used herein is a
combination, physical association and/or solvation of a compound of
the present invention with a solvent molecule. This physical
association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances, the solvate can
be isolated, such as when one or more solvent molecules are
incorporated into the crystal lattice of a crystalline solid. Thus,
"solvate" encompasses both solution-phase and isolatable
solvates.
[0041] Prodrugs of compounds of formula (I) may also be prepared to
as a means to modulate the pharmacokinetic properties, using
various methods known to those skilled in the art. See, e.g.,
Jarkko Rautio and coworkers in Nature Reviews Drug Discovery,
7:255-270 (2008), which is hereby incorporated by reference. In the
case of drugs containing an amine moiety, a variety of prodrug
approaches have been reviewed by A. L. Simplicio, Molecules,
13:519-547 (2008), which is hereby incorporated by reference. More
specifically, (alkoxycarbonyloxy)alkyl carbamates, (acyloxy)alkyl
carbamates, and (oxodioxolenyl)alkyl carbamates have been reported
as effective prodrug strategies for amines by Zhong Li, Bioorg.
Med. Chem. Lett., 7:2909-2912 (1997); J. Alexander, J. Med. Chem.,
34:78-81 (1991); J. Alexander, J. Med. Chem., 31:318-322 (1988);
and J. Alexander, J. Med. Chem., 39:480-486 (1996), all of which
are incorporated by reference herein. (Acyloxy)alkyl carbamates
have also been reported as prodrug analogs for drugs having an
amide group (--CONH--). See, International Patent Publication No.
WO-2005/028473 which is hereby incorporated by reference.
N-Methylenephosphate disodium salt analogs have also been reported
as effective prodrugs for drugs having an amide group (--CONH--) as
well as other functional groups. See, e.g., International Patent
Publication No. WO-2011/002999; R. Singh, "Discovery and
Development of Spleen Tyrosine Kinase (SYK) Inhibitors", J. Med.
Chem., online publication date: Jan. 18, 2012; Y. Ueda, Bioorg.
Med. Chem. Lett., 13:3669-3372 (2003); and International Patent
Publication No. WO-2007/014846; all of which are incorporated by
reference herein. In one embodiment, the prodrug is a diester of
formula (I). In another embodiment, the diester is C(O))(C.sub.1 to
C.sub.6 alkyl)OC(O)(C.sub.1 to C.sub.1 alkyl). In a further
embodiment, the diester is a C(O)OC(CH.sub.3)OC(O)CH.sub.3 or
C(O)OCH.sub.2OC(O)CH.sub.3 prodrug.
[0042] Some compounds within the present invention possess one or
more chiral centers, and the present invention includes each
separate enantiomer of such compounds as well as mixtures of the
enantiomers. Where multiple chiral centers exist in compounds of
the present invention, the invention includes each possible
combination of chiral centers within a compound, as well as all
possible enantiomeric mixtures thereof. All chiral, diastereomeric,
and racemic forms of a structure are intended, unless the specific
stereochemistry or isomeric form is specifically indicated. It is
well known in the art how to prepare optically active forms, such
as by resolution of racemic forms or by synthesis from optically
active starting materials.
[0043] The following definitions are used in connection with the
compounds described herein. In general, the number of carbon atoms
present in a given group is designated "C.sub.x to C.sub.y", where
x and y are the lower and upper limits, respectively. The carbon
number as used in the definitions herein refers to carbon backbone
and carbon branching, but does not include carbon atoms of the
substituents, such as alkoxy substitutions and the like. Unless
indicated otherwise, the nomenclature of substituents that are not
explicitly defined herein are determined by naming from left to
right the terminal portion of the functionality followed by the
adjacent functionality toward the point of attachment. As used
herein, "optionally substituted" means that at least 1 hydrogen
atom of the optionally substituted group has been replaced.
[0044] "Alkyl" refers to a hydrocarbon chain that may be straight
or branched, or to a hydrocarbon group that consists of or contains
a cyclic alkyl radical. In one embodiment, an alkyl contains 1 to 8
(inclusive) carbon atoms or integers or ranges there between. In
another embodiment, an alkyl contains 1 to 7 (inclusive) carbon
atoms or ranges there between. In a further embodiment, an alkyl
contains 1 to 6 (inclusive) carbon atoms. In yet another
embodiment, an alkyl contains 1 to 5 (inclusive) carbon atoms. In
still a further embodiment, an alkyl contains 1 to 4 (inclusive)
carbon atoms. Examples of alkyl groups that are hydrocarbon chains
include, but are not limited to, methyl, ethyl, propyl, butyl,
pentyl, hexyl, and heptyl, where all isomers of these examples are
contemplated. Examples of alkyl groups that consist of or contain a
cyclic alkyl radical include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, 3,3-dimethylcyclobutyl,
(cyclopropyl)methyl, and (cyclopentyl)methyl. An alkyl can be
unsubstituted or substituted with one or more groups including,
without limitation, halogen, OH, NH.sub.2, N(C.sub.1 to C.sub.3
alkyl)C(O)(C.sub.1 to C.sub.6 alkyl), NHC(O)(C.sub.1 to C.sub.6
alkyl), NHC(O)H, C(O)NH.sub.2, C(O)NH(C.sub.1 to C.sub.6 alkyl),
C(O)N(C.sub.1 to C.sub.6 alkyl)(C.sub.1 to C.sub.6 alkyl), CN,
C.sub.1 to C.sub.6 alkoxy, C(O)OH, C(O)O(C.sub.1 to C.sub.6 alkyl),
C(O)(C.sub.1 to C.sub.6 alkyl), aryl, heteroaryl, NH(C.sub.1 to
C.sub.6 alkyl), N(C.sub.1 to C.sub.6 alkyl)(C.sub.1 to C.sub.6
alkyl), OC(O)(C.sub.1 to C.sub.6 alkyl), and NO.sub.2. In one
embodiment, the substituted alkyl is CH.sub.2OH.
[0045] "Alkenyl" refers to hydrocarbon chain which is straight or
branched and contains at least one degree of unsaturation (i.e.,
with one or more carbon-carbon double bonds), or to a hydrocarbon
group that consists of or contains a cyclic alkenyl radical. Each
alkenyl double bond may exist in the E or Z conformation. In one
embodiment, an alkenyl contains 2 to about 8 (inclusive) carbon
atoms or integers or ranges there between. In another embodiment,
an alkenyl contains 2 to 7 (inclusive) carbon atoms. In a further
embodiment, an alkenyl contains 2 to 6 (inclusive) carbon atoms. In
yet another embodiment, an alkenyl contains 2 to 5 (inclusive)
carbon atoms. In still a further embodiment, an alkenyl contains 2
to 4 (inclusive) carbon atoms. An alkenyl contains at least 1
double bond. In one embodiment, the alkenyl may contain 1 to 4
double bonds, or integers there between. Examples of alkenyl
hydrocarbon chain include, but are not limited to, ethene, propene,
butene, pentene, hexene, heptene, and octene. Examples of alkenyl
that consist of or contain a cyclic alkenyl radical include, but
are not limited to, cyclopentene, and cyclohexene. An alkenyl can
be unsubstituted or substituted with one or more groups including,
without limitation, halogen, OH, NH.sub.2, N(C.sub.1 to C.sub.3
alkyl)C(O)(C.sub.1 to C.sub.6 alkyl), NHC(O)(C.sub.1 to C.sub.6
alkyl), NHC(O)H, C(O)NH.sub.2, C(O)NH(C.sub.1 to C.sub.6 alkyl),
C(O)N(C.sub.1 to C.sub.6 alkyl)(C.sub.1 to C.sub.6 alkyl), CN,
C.sub.1 to C.sub.6 alkoxy, C(O)OH, C(O)O(C.sub.1 to C.sub.6 alkyl),
C(O)(C.sub.1 to C.sub.6 alkyl), aryl, heteroaryl, NH(C.sub.1 to
C.sub.6 alkyl), N(C.sub.1 to C.sub.6 alkyl)(C.sub.1 to C.sub.6
alkyl), OC(O)(C.sub.1 to C.sub.6 alkyl), and NO.sub.2.
[0046] "Alkynyl" refers to a hydrocarbon chain which is straight or
branched chain and contains at least one degree of unsaturation,
i.e., with one or more carbon-carbon triple bond. In one
embodiment, an alkynyl contains 2 to about 8 (inclusive) carbon
atoms or integers or ranges there between. In another embodiment,
an alkynyl contains 2 to 7 (inclusive) carbon atoms. In a further
embodiment, an alkynyl contains 2 to 6 (inclusive) carbon atoms. In
yet another embodiment, an alkynyl contains 2 to 5 (inclusive)
carbon atoms. In still a further embodiment, an alkynyl contains 2
to 4 (inclusive) carbon atoms. An alkynyl contains at least 1
triple bond. In one embodiment, the alkynyl may contain 1 to 4
triple bonds, or integers there between. Examples of alkynyl
include, but are not limited to, ethyne, propyne, butyne, pentyne,
hexyne, heptyne, and octyne. An alkynyl can be unsubstituted or
substituted with one or more groups including, without limitation,
halogen, OH, NH.sub.2, N(C.sub.1 to C.sub.3 alkyl)C(O)(C.sub.1 to
C.sub.6 alkyl), NHC(O)(C.sub.1 to C.sub.6 alkyl), NHC(O)H,
C(O)NH.sub.2, C(O)NH(C.sub.1 to C.sub.6 alkyl), C(O)N(C.sub.1 to
C.sub.6 alkyl)(C.sub.1 to C.sub.6 alkyl), CN, C.sub.1 to C.sub.6
alkoxy, C(O)OH, C(O)O(C.sub.1 to C.sub.6 alkyl), C(O)(C.sub.1 to
C.sub.6 alkyl), aryl, heteroaryl, NH(C.sub.1 to C.sub.6 alkyl),
N(C.sub.1 to C.sub.6 alkyl)(C.sub.1 to C.sub.6 alkyl),
OC(O)(C.sub.1 to C.sub.6 alkyl), and NO.sub.2.
[0047] "Alkoxy" refers to (alkyl)O, where the alkyl is optionally
substituted and is defined above. In one embodiment, an alkoxy
contains 1 to 8 (inclusive) carbon atoms or integers or ranges
there between. In another embodiment, an alkoxy contains 1 to 7
(inclusive) carbon atoms or ranges there between. In a further
embodiment, an alkoxy contains 1 to 6 (inclusive) carbon atoms. In
yet another embodiment, an alkoxy contains 1 to 5 (inclusive)
carbon atoms. In still a further embodiment, an alkoxy contains 1
to 4 (inclusive) carbon atoms. Examples of alkoxy include, but are
not limited to, methoxy, ethoxy, propoxy, and butoxy. The alkyl
radical of an alkoxy group can be unsubstituted or substituted as
defined above for "alkyl".
[0048] "Hydroxyalkyl" refers to (alkyl)OH, where the alkyl is
optionally substituted and is defined above. The OH moiety of the
hydroxyalkyl may be bound to any carbon atom, for example, any one
of the internal carbon atoms or the terminal carbon atom of a
hydrocarbon alkyl chain. In one embodiment, a hydroxyalkyl contains
1 to 8 (inclusive) carbon atoms or integers or ranges there
between. In another embodiment, a hydroxyalkyl contains 1 to 7
(inclusive) carbon atoms or ranges there between. In a further
embodiment, a hydroxyalkyl contains 1 to 6 (inclusive) carbon
atoms. In yet another embodiment, a hydroxyalkyl contains 1 to 5
(inclusive) carbon atoms. In still a further embodiment, a
hydroxyalkyl contains 1 to 4 (inclusive) carbon atoms. Examples of
a hydroxyalkyl include, but are not limited to, CH.sub.2OH,
CH.sub.2CH.sub.2OH, CH(OH)CH.sub.3, CH.sub.2CH.sub.2CH.sub.2OH,
CH.sub.2CH(OH)CH.sub.3, CH(OH)CH.sub.2CH.sub.3,
C(OH)(CH.sub.3).sub.2, (2-hydroxy)-cyclopentyl,
(3-hydroxy)-cyclobutyl, and the like.
[0049] "Cyanoalkyl" refers to (alkyl)CN, where the alkyl is
optionally substituted and is defined above. The CN moiety of the
cyanoalkyl may be bound to any carbon atom; for example, any one of
the internal carbon atoms or the terminal carbon atom of a
hydrocarbon alkyl chain. In one embodiment, a cyanoalkyl contains 1
to 8 (inclusive) carbon atoms or integers or ranges there between.
In another embodiment, a cyanoalkyl contains 1 to 7 (inclusive)
carbon atoms or ranges there between. In a further embodiment, a
cyanoalkyl contains 1 to 6 (inclusive) carbon atoms. In yet another
embodiment, a cyanoalkyl contains 1 to 5 (inclusive) carbon atoms.
In still a further embodiment, a cyanoalkyl contains 1 to 4
(inclusive) carbon atoms. Examples of cyanoalkyl include, but are
not limited to, CH.sub.2CN, CH.sub.2CH.sub.2CN, CH(CN)CH.sub.3,
CH.sub.2CH.sub.2CH.sub.2CN, CH.sub.2CH(CN)CH.sub.3,
CH(CN)CH.sub.2CH.sub.3, C(CN)(CH.sub.3).sub.2,
(2-cyano)-cyclopentyl, (3-cyano)-cyclobutyl, and the like.
[0050] "Aryl" refers to an aromatic hydrocarbon group containing
carbon atoms. In one embodiment, the aryl contains 6, 7 or 8 carbon
atoms, and is phenyl or is an aromatic or partly aromatic bicyclic
group. In a further embodiment, the aryl is a phenyl group. In
another embodiment, the aryl is naphthyl (such as .alpha.-naphthyl
or .beta.-naphthyl), 1,2,3,4-tetrahydronaphthyl, or indanyl. An
aryl group can be unsubstituted or substituted with one or more
groups including, without limitation, halogen, OH, NH.sub.2,
N(C.sub.1 to C.sub.3 alkyl)C(O)(C.sub.1 to C.sub.6 alkyl),
NHC(O)(C.sub.1 to C.sub.6 alkyl), NHC(O)H, C(O)NH.sub.2,
C(O)NH(C.sub.1 to C.sub.6 alkyl), C(O)N(C.sub.1 to C.sub.6
alkyl)(C.sub.1 to C.sub.6 alkyl), CN, C.sub.1 to C.sub.6 alkoxy,
C(O)OH, C(O)O(C.sub.1 to C.sub.6 alkyl), C(O)(C.sub.1 to C.sub.6
alkyl), aryl, heteroaryl, NH(C.sub.1 to C.sub.6 alkyl), N(C.sub.1
to C.sub.6 alkyl)(C.sub.1 to C.sub.6 alkyl), OC(O)(C.sub.1 to
C.sub.6 alkyl), and NO.sub.2. In one embodiment, an aryl is
substituted with one or more halogen, OH, CN, NH.sub.2, C.sub.1 to
C.sub.6 alkylamino, C.sub.1 to C.sub.6 alkyl substituted with OH,
C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 haloalkyl, OCF.sub.3,
SO.sub.2(C.sub.1 to C.sub.6 alkyl), or NHSO.sub.2(C.sub.1 to
C.sub.6 alkyl). In another embodiment, an aryl is substituted with
one halogen, OH, CN, NH.sub.2, C.sub.1 to C.sub.6 alkylamino,
C.sub.1 to C.sub.6 alkyl substituted with OH, C.sub.1 to C.sub.6
alkoxy, CF.sub.3, OCF.sub.3, SO.sub.2CH.sub.3, NHCOCH.sub.3, or
NHSO.sub.2CH.sub.3. In a further embodiment, an aryl is substituted
with one halogen, OH, CN, N(CH.sub.3).sub.2, CH.sub.2OH, OCH.sub.3,
OCF.sub.3, CF.sub.3, SO.sub.2CH.sub.3, NHCOCH.sub.3, or
NHSO.sub.2CH.sub.3.
[0051] "Halogen" refers to F, Cl, Br and I.
[0052] The term "heteroatom" refers to a sulfur, nitrogen, or
oxygen atom.
[0053] "Heteroaryl" refers to a monocyclic aromatic 5- or
6-membered ring containing at least one ring heteroatom. In one
embodiment, the heteroaryl contains 1 to 5 carbon atoms (inclusive)
or integers or ranges there between. In a further embodiment, the
heteroaryl contains 2 to 5 carbon atoms (inclusive). In another
embodiment, the heteroaryl contains 3 to 5 carbon atoms
(inclusive). In still a further embodiment, the heteroaryl contains
4 or 5 carbon atoms. "Heteroaryl" also refers to bicyclic aromatic
ring systems wherein a heteroaryl group as just described is fused
to at least one other cyclic moiety. In one embodiment, a phenyl
radical is fused to a 5- or 6-membered monocyclic heteroaryl to
form the bicyclic heteroaryl. In another embodiment, a cyclic alkyl
is fused to a monocyclic heteroaryl to form the bicyclic
heteroaryl. In yet a further embodiment, the bicyclic heteroaryl is
a pyridine fused to a 5- or 6-membered monocyclic heteroaryl. In
another embodiment, the bicyclic heteroaryl is a pyrimidine fused
to a 5- or 6-membered monocyclic heteroaryl. In yet a further
embodiment, the bicyclic heteroaryl is a pyridazine fused to a 5-
or 6-membered monocyclic heteroaryl. In still another embodiment,
the heteroaryl ring has 1 or 2 nitrogen atoms in the ring. In a
further embodiment, the heteroaryl ring has 1 nitrogen atom and 1
oxygen atom. In yet another embodiment, the heteroaryl ring has 1
nitrogen atom and 1 sulfur atom. Examples of heteroaryl groups
include, without limitation, furan, thiophene, indole, azaindole,
oxazole, thiazole, isoxazole, isothiazole, imidazole, pyridine,
pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole,
1,3,4-oxadiazole, 1,2,4-triazole, tetrazole, benzoxazole,
benzothiazole, benzofuran, benzisoxazole, benzimidazole,
azabenzimidazole, indazole, quinazoline, quinoline, and
isoquinoline. A heteroaryl may be unsubstituted or substituted with
one or more groups including, without limitation, halogen, OH,
NH.sub.2, N(C.sub.1 to C.sub.3 alkyl)C(O)(C.sub.1 to C.sub.6
alkyl), NHC(O)(C.sub.1 to C.sub.6 alkyl), NHC(O)H, C(O)NH.sub.2,
C(O)NH(C.sub.1 to C.sub.6 alkyl), C(O)N(C.sub.1 to C.sub.6
alkyl)(C.sub.1 to C.sub.6 alkyl), CN, C.sub.1 to C.sub.6 alkoxy,
C(O)OH, C(O)O(C.sub.1 to C.sub.6 alkyl), C(O)(C.sub.1 to C.sub.6
alkyl), aryl, heteroaryl, NH(C.sub.1 to C.sub.6 alkyl), N(C.sub.1
to C.sub.6 alkyl)(C.sub.1 to C.sub.6 alkyl), OC(O)(C.sub.1 to
C.sub.6 alkyl), and NO.sub.2. In one embodiment, a heteroaryl is
substituted with one or more halogen, OH, CN, NH.sub.2, C.sub.1 to
C.sub.6 alkylamino, C.sub.1 to C.sub.6 alkyl substituted with OH,
C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 haloalkyl, OCF.sub.3,
SO.sub.2(C.sub.1 to C.sub.6 alkyl), NHCOCH.sub.3, or
NHSO.sub.2(C.sub.1 to C.sub.6 alkyl). In another embodiment, a
heteroaryl is substituted with one halogen, OH, CN,
N(CH.sub.3).sub.2, CH.sub.2OH, OCH.sub.3, OCF.sub.3, CF.sub.3,
SO.sub.2CH.sub.3, NHCOCH.sub.3, or NHSO.sub.2CH.sub.3.
[0054] "Heterocycle" refers to a monocyclic or bicyclic group in
which at least 1 ring atom is a heteroatom. A heterocycle may be
saturated or partially saturated. In one embodiment, the
heterocycle contains 3 to 7 carbon atoms (inclusive) or integers or
ranges there between. In a further embodiment, the heterocycle
contains 4 to 7 carbon atoms (inclusive). In another embodiment,
the heterocycle contains 4 to 6 carbon atoms (inclusive). In still
a further embodiment, the heterocycle contains 5 or 6 carbon atoms
(inclusive). Examples of heterocycles include, but are not limited,
to aziridine, oxirane, thiirane, morpholine, thiomorpholine,
pyrroline, pyrrolidine, azepane, dihydrofuran, tetrahydrofuran,
dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine,
1,2,3,6-tetrahydropyridine-1-yl, tetrahydropyran, pyran, thiane,
thiine, piperazine, homopiperazine, oxazine, azecane,
tetrahydroquinoline, perhydroisoquinoline,
5,6-dihydro-4H-1,3-oxazin-2-yl, 2,5-diazabicyclo[2.2.1]heptane,
2,5-diazabicyclo[2.2.2]octane, 3,6-diazabicyclo[3.1.1]heptane,
3,8-diazabicyclo[3.2.1]octane, 6-oxa-3,8-diazabicyclo[3.2.1]octane,
7-oxa-2,5-diazabicyclo[2.2.2]octane,
2,7-dioxa-5-azabicyclo[2.2.2]octane,
2-oxa-5-azabicyclo[2.2.1]heptane-5-yl,
2-oxa-5-azabicyclo[2.2.2]octane,
3,6-dioxa-8-azabicyclo[3.2.1]octane,
3-oxa-6-azabicyclo[3.1.1]heptane,
3-oxa-8-azabicyclo[3.2.1]octan-8-yl,
5,7-dioxa-2-azabicyclo[2.2.2]octane,
6,8-dioxa-3-azabicyclo[3.2.1]octane,
6-oxa-3-azabicyclo[3.1.1]heptane,
8-oxa-3-azabicyclo[3.2.1]octan-3-yl,
2,5-diazabicyclo[2.2.1]heptane-5-yl, 6-azabicyclo[3.2.1]oct-6-yl,
8-azabicyclo[3.2.1]octan-8-yl,
3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl,
9-oxa-3-azabicyclo[3.3.1]nonan-3-yl,
3-oxa-9-azabicyclo[3.3.1]nonan-9-yl,
3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl,
3,4-dihydro-2H-1,4-benzoxazin-7-yl, thiazine, dithiane, and
dioxane. In another embodiment, the heterocycle contains 1 or 2
nitrogen atoms. In a further embodiment, the heterocycle contains 1
or 2 nitrogen atoms and 3 to 6 carbon atoms. In yet another
embodiment, the heterocycle contains 1 or 2 nitrogen atoms, 3 to 6
carbon atoms, and 1 oxygen atom. In still a further embodiment, the
heterocycle is morpholine. In one embodiment, the heterocycle is
morpholine and is substituted with one or more C.sub.1 to C.sub.3
alkyl. In another embodiment, the heterocycle is morpholine and 2
carbons of the heterocycle are joined to form a 4- or 5-membered
ring. A heterocycle may be unsubstituted or substituted with one or
more groups including, without limitation, halogen, OH, NH.sub.2,
N(C.sub.1 to C.sub.3 alkyl)C(O)(C.sub.1 to C.sub.6 alkyl),
NHC(O)(C.sub.1 to C.sub.6 alkyl), NHC(O)H, C(O)NH.sub.2,
C(O)NH(C.sub.1 to C.sub.6 alkyl), C(O)N(C.sub.1 to C.sub.6
alkyl)(C.sub.1 to C.sub.6 alkyl), CN, C.sub.1 to C.sub.6 alkoxy,
C(O)OH, C(O)O(C.sub.1 to C.sub.6 alkyl), C(O)(C.sub.1 to C.sub.6
alkyl), aryl, heteroaryl, NH(C.sub.1 to C.sub.6 alkyl), N(C.sub.1
to C.sub.6 alkyl)(C.sub.1 to C.sub.6 alkyl), OC(O)(C.sub.1 to
C.sub.6 alkyl), and NO.sub.2. In one embodiment, a heterocycle is
substituted with one or more halogen, OH, CN, NH.sub.2, C.sub.1 to
C.sub.6 alkylamino, C.sub.1 to C.sub.6 alkyl substituted with OH,
C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 haloalkyl, OCF.sub.3,
SO.sub.2(C.sub.1 to C.sub.6 alkyl), NHCOCH.sub.3, or
NHSO.sub.2(C.sub.1 to C.sub.6 alkyl). In another embodiment, a
heterocycle is substituted with one F, OH, CN, NH.sub.2,
N(CH.sub.3).sub.2, CH.sub.2OH, OCH.sub.3, OCF.sub.3, CF.sub.3,
SO.sub.2CH.sub.3, NHCOCH.sub.3, or NHSO.sub.2CH.sub.3.
[0055] "C.sub.1 to C.sub.6 haloalkyl" refers to a C.sub.1 to
C.sub.6 alkyl group, as defined above, wherein one or more of the
C.sub.1 to C.sub.6 alkyl group's hydrogen atoms has been replaced
with F, Cl, Br, or I. Each substitution can be independently
selected from F, Cl, Br, or I. Representative examples of an
C.sub.1 to C.sub.6 haloalkyl group include, but are not limited to,
CH.sub.2F, CF.sub.3, CH.sub.2CF.sub.3, and the like.
[0056] "Alkylthio" refers to (alkyl)S, where the alkyl is
optionally substituted and is defined above. In one embodiment, an
alkylthio contains 1 to 8 (inclusive) carbon atoms or integers or
ranges there between. Examples of alkylthio include, but are not
limited to, SCH.sub.3, SCH.sub.2CH.sub.3,
SCH.sub.2CH.sub.2CH.sub.3, and
SCH.sub.2CH.sub.2CH.sub.2CH.sub.3.
[0057] "Aryloxy" refers to (aryl)O, where the aryl is defined above
and is optionally substituted as described above. An aryloxy group
is attached through the oxygen atom moiety. Examples of aryloxy
include, but are not limited to, phenoxy and
pentafluorophenoxy.
[0058] "Heteroaryloxy" refers to (heteroaryl)O, where the
heteroaryl is optionally substituted and is defined above. The
heteroaryloxy moiety is bound through the oxygen atom moiety.
Examples of heteroaryloxy include, but are not limited to,
(3-pyridyl)oxy and (4-pyridyl)oxy.
[0059] "Heterocycle-oxy" refers to (heterocycle)O, where the
heterocycle is optionally substituted and is defined above. The
heterocycle-oxy moiety is bound through the oxygen atom. Examples
of heterocycleoxy include, but are not limited to,
(4-piperidinyl)oxy.
[0060] "Alkylsulfonyl" refers to an (alkyl)SO.sub.2, group, which
is bound through the SO.sub.2 moiety. The alkyl group is defined
and optionally substituted as described above. Examples of
alkylsulfonyl include, but are not limited to, CH.sub.3SO.sub.2,
CH.sub.3CH.sub.2CH.sub.2SO.sub.2, CH.sub.3CH(CH.sub.3)SO.sub.2,
CH.sub.3CH.sub.2CH.sub.2CH.sub.2SO.sub.2,
CH.sub.3CH(CH.sub.3)CH.sub.2SO.sub.2, (CH.sub.3).sub.3CSO.sub.2,
and the like.
[0061] "Alkylsulfonylalkyl" refers to an (alkyl)SO.sub.2(alkyl)
group, which is bound through one of the alkyl groups. The alkyl
group is defined and optionally substituted as described above. The
alkyl groups may be the same or different. Examples of
alkylsulfonylalkyl include, but are not limited to,
3-(methylsulfonyl)propyl and 3-(methylsulfonyl)cyclopentyl.
[0062] "Alkylamino" refers to an NH or N group, the nitrogen atom
of said group being attached to 1 or 2 alkyl substituents,
respectively, where alkyl is as defined above. The alkylamino is
bound through the nitrogen atom of the group. In one embodiment,
alkylamino refers to a (alkyl)NH group. In another embodiment,
alkylamino refers to a (alkyl)(alkyl)N group, i.e., a
"dialkylamino". When the nitrogen atom is bound to 2 alkyls, each
alkyl group may be independently selected. In another embodiment,
two alkyl groups on the nitrogen atom may be taken together with
the nitrogen to which they are attached to form a 3- to 7-membered
nitrogen-containing heterocycle wherein up to two of the carbon
atoms of the heterocycle can be replaced with N(H), N(C.sub.1 to
C.sub.6 alkyl), N(aryl), N(heteroaryl), O, S, S(O), or S(O).sub.2.
Examples of alkylamino include, but are not limited to CH.sub.3NH,
CH.sub.3CH.sub.2NH, CH.sub.3CH.sub.2CH.sub.2NH,
CH.sub.3CH.sub.2CH.sub.2CH.sub.2NH, (CH.sub.3).sub.2CHNH,
(CH.sub.3).sub.2CHCH.sub.2NH, CH.sub.3CH.sub.2CH(CH.sub.3)NH,
(CH.sub.3).sub.3CNH, N(CH.sub.3).sub.2,
N(CH.sub.2CH.sub.3)(CH.sub.3), N(CH.sub.2CH.sub.3).sub.2,
N(CH.sub.2CH.sub.2CH.sub.3).sub.2,
N(CH.sub.2CH.sub.2CH.sub.2CH.sub.3).sub.2,
N(CH(CH.sub.3).sub.2)(CH.sub.3), and the like.
[0063] "Aminoalkyl" refers to an alkyl group having an NH.sub.2
substituent. The aminoalkyl is bound through one carbon atom of the
group. That is, alkylamino refers to a NH.sub.2(alkyl) group.
Examples of aminoalkyl include, but are not limited to
CH.sub.2NH.sub.2, CH.sub.2CH.sub.2NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2,
C(CH.sub.3).sub.2NH.sub.2, C(CH.sub.3).sub.2CH.sub.2NH.sub.2, and
the like.
[0064] "Alkylaminoalkyl" refers to an (alkyl)NH(alkyl) group, the
nitrogen atom of being attached to 2 alkyl substituents,
respectively, as defined above, and where the group is bound
through one of the alkyl groups. Each of the alkyl groups may be
independently selected and substituted as described above. In
another embodiment, the alkyl groups may be taken together with the
nitrogen to which they are attached to form a 3- to 7-membered
nitrogen containing heterocycle wherein up to two of the carbon
atoms of the heterocycle can be replaced with N(H), N(C.sub.1 to
C.sub.6 alkyl), N(aryl), N(heteroaryl), O, S, S(O), or S(O).sub.2.
Examples of alkylaminoalkyl include, but are not limited to
CH.sub.3NHCH.sub.2, CH.sub.3NHCH.sub.2CH.sub.2,
CH.sub.3NHCH(CH.sub.3), CH.sub.3CH.sub.2NHCH.sub.2,
CH.sub.3CH.sub.2NHCH.sub.2CH.sub.2, CH.sub.3CH.sub.2NHCH(CH.sub.3),
and the like.
[0065] "Dialkylaminoalkyl" refers to an (alkyl).sub.2N(alkyl)
group, the nitrogen atom of being attached to 3 alkyl substituents,
respectively, as defined above, and where the group is bound
through one of the alkyl groups. Each of the alkyl groups may be
independently selected and substituted as described above. In
another embodiment, two of the alkyl groups may be taken together
with the nitrogen to which they are attached to form a 3- to
7-membered nitrogen containing heterocycle wherein up to two of the
carbon atoms of the heterocycle can be replaced with N(H),
N(C.sub.1 to C.sub.6 alkyl), N(aryl), N(heteroaryl), O, S, S(O), or
S(O).sub.2. Examples of dialkylaminoalkyl include, but are not
limited to (CH.sub.3).sub.2NCH.sub.2,
(CH.sub.3).sub.2NCH.sub.2CH.sub.2, (CH.sub.3).sub.2NCH(CH.sub.3),
(CH.sub.3CH.sub.2).sub.2NCH.sub.2,
(CH.sub.3CH.sub.2).sub.2NCH.sub.2CH.sub.2,
(CH.sub.3CH.sub.2).sub.2NCH(CH.sub.3),
(CH.sub.3)(CH.sub.3CH.sub.2)NCH.sub.2, and the like.
[0066] "Acylamino" refers to an (aryl)NH group, where aryl is
optionally substituted and defined as above. The arylamino is bound
through the nitrogen atom. Examples of arylamino include, but are
not limited to, phenyl-amino.
[0067] "Heteroarylamino" refers to a (heteroaryl)NH group, where
heteroaryl is optionally substituted and defined as above. The
heteroarylamino is bound through the amino nitrogen atom. Examples
of heteroarylamino include, but are not limited to
(pyridin-2-yl)amino and (pyrimidin-2-yl)amino
[0068] "Heterocycle-amino" refers to a (heterocycle)NH group, where
heterocycle is optionally substituted and defined as above.
Examples of heterocycle-amino include, but are not limited to
(piperidin-4-yl)amino.
[0069] "Alkylcarbonylamino" refers to an (alkyl)C(O)NH group, which
is bound through the nitrogen atom. The alkyl group is defined and
optionally substituted as described above. Examples of
alkylcarbonylamino include, but are not limited to, CH.sub.3CONH,
CH.sub.3CH.sub.2CONH, CH.sub.3CH.sub.2CH.sub.2CONH,
CH.sub.3CH(CH.sub.3)CONH, and the like.
[0070] "Alkylsulfonylamino" refers to an (alkyl)SO.sub.2NH group
which is bound through the nitrogen atom. The alkyl group is
defined and optionally substituted as described above. Examples of
alkylsulfonylamino include, but are not limited to
CH.sub.3SO.sub.2NH, CH.sub.3CH.sub.2SO.sub.2NH,
CH.sub.3CH.sub.2CH.sub.2SO.sub.2NH, CH.sub.3CH(CH.sub.3)SO.sub.2NH,
and the like.
[0071] "Alkylaminocarbonyl" refers to an (alkyl)NHC(O) group, which
is bound through the carbonyl moiety. The alkyl group is defined
and optionally substituted as described above. Examples of
alkylaminocarbonyl include, but are not limited to, CH.sub.3NHCO,
CH.sub.3CH.sub.2NHCO, CH.sub.3CH.sub.2CH.sub.2NHCO,
CH.sub.3CH(CH.sub.3)NHCO, and the like.
[0072] "Alkylaminosulfonyl" refers to an (alkyl)NHSO.sub.2 group,
which is bound through the sulfur atom. The alkyl group is defined
and optionally substituted as described above. Examples of
alkylaminosulfonyl include, but are not limited to,
CH.sub.3NHSO.sub.2, CH.sub.3CH.sub.2NHSO.sub.2,
CH.sub.3CH.sub.2CH.sub.2NHSO.sub.2, CH.sub.3CH(CH.sub.3)NHSO.sub.2,
and the like.
[0073] "Arylaminocarbonyl" refers to an (aryl)NHC(O) group, which
is bound through the carbon atom of the carbonyl moiety. The aryl
group is defined and optionally substituted as described above.
Examples of arylaminocarbonyl include, but are not limited to
phenyl-NHC(O)--.
[0074] "Heteroarylaminocarbonyl" refers to an (heteroaryl)NHC(O)
group, which is bound through the carbon atom of the carbonyl
moiety. The heteroaryl group is defined and optionally substituted
as described above. Examples of heteroarylaminocarbonyl include,
but are not limited to (pyridine-4-yl)NHC(O).
[0075] "Heterocycleaminocarbonyl" refers to an (heterocycle)NHC(O)
group, which is bound through the carbonyl moiety. The heterocycle
group is defined and optionally substituted as described above.
Examples of heterocycleaminocarbonyl include, but are not limited
to (tetrahydro-2H-pyran-4-yl)NHC(O).
[0076] A"patient" or "subject" is a mammal, e.g., a human or a
veterinary patient or subject, e.g., mouse, rat, guinea pig, dog,
cat, horse, cow, pig, or non-human primate, such as a monkey,
chimpanzee, baboon or gorilla.
[0077] The term "treating" or "treatment" is meant to encompass
administering to a subject a compound of the present invention for
the purposes of amelioration of one or more symptoms of a disease
or disorder, including palliative care. A"therapeutically effective
amount" refers to the minimum amount of the active compound which
effects treatment.
[0078] The following abbreviations are used herein and have the
indicated definitions: ACN is acetonitrile; BCA is bicinchoninic
acid; bid po means twice daily by mouth; conc is concentrated; DMSO
is dimethylsulfoxide; DCC is dicyclohexylcarbodiimide; DCM is
dichloromethane; DIPEA is diisopropylethylamine; DMF is
N,N-dimethylformamide; dppf is
1,1'-bis(diphenylphosphino)ferrocene; DTT is dithiothreitol;
EDC.HCl is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride; EDTA is ethylenediamine tetraacetic acid; EGTA is
ethylene glycol tetraacetic acid; ELISA is enzyme-linked
immunosorbent assay; EtOH is ethanol; ESI is electrospray
ionization; EI is electron impact ionization; HATU is
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium
hexafluorophosphate methanaminium; HEPES is
(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; HPCD is
hydroxypropyl-.beta.-cyclodextrin; HPLC is high performance liquid
chromatography; Hz is hertz; HOAt is 1-hydroxy-7-azabenzotriazole;
HOBt is 1-hydroxy benzotriazole; KOAc is potassium acetate; LC is
liquid chromatography; MS is mass spectroscopy; MeOH is methanol;
MHz is megahertz; mM is millimolar; mL is milliliter; min is
minutes; mol is moles; M.sup.+ is molecular ion; [M+H].sup.+ is
protonated molecular ion; N is normality; NMR is nuclear magnetic
resonance; PIP2 is 5-bisphosphate; PBS is phosphate buffered
saline; PH is pleckstrin homology; PMSF is phenylmethanesulfonyl
fluoride; PPh.sub.3 is triphenylphosphine; PTSA is
para-toluenesulphonic acid; psi is pound per square inch; PPM is
parts per million; qd po means daily by mouth; rt is room
temperature; RT is retention time; TLC is thin layer
chromatography; TFA is trifluoroacetic acid; TEA is triethylamine;
THF is tetrahydrofuran; TMS is tetramethylsilane; and XTT is sodium
2,3,-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-2H-t-
etrazolium inner salt.
[0079] The words "comprise", "comprises", and "comprising" are to
be interpreted inclusively rather than exclusively. The works
"consist", "consisting", and its variants, are to be interpreted
exclusively, rather than inclusively.
[0080] As used herein, the term "about" means a variability of 10%
from the reference given, unless otherwise specified.
[0081] Methods useful for making the compounds of Formula (I) are
set forth in the Examples below and generalized in Schemes I-V. One
of skill in the art will recognize that Schemes I-V can be adapted
to produce the other compounds of Formula (I) and pharmaceutically
acceptable salts or prodrugs of compounds of Formula (I) according
to the present invention.
##STR00029##
[0082] Scheme I provides the preparation of the compounds (I) of
the invention. In this scheme, the noted R.sup.1-substituted
3-bromo aniline 1a is reacted with chloral hydrate and
hydroxylamine hydrochloride to provide compound 2a. In one
embodiment, the reaction is performed in the presence of about 1
equivalent of chloral hydrate. In another embodiment, the reaction
is performed in the presence of about 3 equivalents of
hydroxylamine hydrochloride. In a further embodiment the reaction
is performed in the presence of Na.sub.2SO.sub.4, HCl, and water.
In yet another embodiment, the reaction is performed at elevated
temperatures. In still a further embodiment, the reaction is
performed at about 90.degree. C. Alternatively, 1a could have a
different leaving group substituent such as 3-chloro in place of
the 3-bromo substituent, with some modifications to subsequent
steps in the synthetic sequence. The hydroxylamine substituent of
compound 2a is then cyclized to form dione compound 3a. This
reaction is performed by adding compound 2a to a solution of
sulfuric acid. In one embodiment, the reaction is conducted at an
elevated temperature. In another embodiment, the reaction is
conducted at a temperature of about 50.degree. C. In a further
embodiment, the temperature of the reaction mixture is raised above
about 50.degree. C. during the reaction. In yet another embodiment,
the temperature of the reaction mixture is raised to about
90.degree. C. The dione ring portion of compound 3a is then opened
to provide carboxylic acid compound 4a. In one embodiment, the ring
is opened using hydrogen peroxide. The ring opening reaction is
typically performed at reduced temperatures. In one embodiment, the
ring opening reaction is performed at about 0.degree. C. In a
further embodiment, the ring opening reaction is performed in the
presence of sodium hydroxide. Carboxylic acid compound 4a is then
cyclized to the corresponding cyclic urea 5a. In one embodiment,
the cyclization is performed using urea. In another embodiment, the
cyclization is performed using an excess of urea. In a further
embodiment, the cyclization is performed using about 10 equivalents
of urea. The cyclization is typically performed at elevated
temperatures. In one embodiment, the cyclization is performed at
about 200.degree. C. The oxo groups of compound 5a are then
replaced with chlorine groups to provide compound 6a. In one
embodiment, compound 5a is reacted with phosphoryl chloride
(POCl.sub.3). In another embodiment, the reaction to form compound
6a is performed in the presence of a base such as triethylamine or
DIPEA. This reaction may be performed at elevated temperatures. In
one embodiment, compound 6a is formed from compound 5a at a
temperature of about 130.degree. C. The chlorine at the 4-position
of compound 6a is then replaced with an optionally substituted
morpholine (R.sup.2) to provide compound 7a. In one embodiment,
compound 6a is reacted with an optionally substituted morpholine.
In another embodiment, compound 6a is reacted with morpholine. The
reaction is typically performed at a reduced temperature. In one
embodiment, compound 7a is formed via compound 6a at a temperature
of about 0.degree. C. Compound 7a is then R.sup.3 substituted at
the 7-position using reagents and conditions understood by those
skilled in the art. In one embodiment, compound 7a is
R.sup.3-substituted by a coupling reaction using R.sup.3B(OH).sub.2
or R.sup.3B(OR).sub.2 to provide compound 8a. In one embodiment,
the R.sup.3-substitution is performed in the presence of a
palladium catalyst such as PdCl.sub.2(PPh.sub.3).sub.2. In another
embodiment, the R.sup.3-substitution is performed at elevated
temperatures. In a further embodiment, the R.sup.3-substitution is
performed at about 90-95.degree. C. In a further embodiment, the
R.sup.3-substitution is carried out in the presence of
Na.sub.2CO.sub.3. In one embodiment, the R.sup.3-substitution is
carried out in a solvent system such as DMF and water. In another
embodiment, the R.sup.3-substitution is carried out in a solvent
system such as toluene, ethanol and water. Compound 8a is then
substituted at the 2-position with a
tert-butoxycarbonyl)amino-pyrimidine group to provide compound 9a.
In one embodiment, the 2-position of compound 8a is substituted
using 2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid. In
another embodiment, the substitution is performed in the presence
of a palladium catalyst such as Pd(PPh.sub.3).sub.4 or
PdCl.sub.2(PPh.sub.3).sub.2. In a further embodiment, the
pyrimidine substitution is performed at elevated temperatures of
about 90 to about 110.degree. C. In still another embodiment, the
pyrimidine substitution is performed using Pd(PPh.sub.3).sub.4 in
the presence of K.sub.3PO.sub.4. In yet a further embodiment, the
pyrimidine substitution is performed using
PdCl.sub.2(PPh.sub.3).sub.2 in the presence of Cs.sub.2CO.sub.3. In
one embodiment, the R.sup.3-substitution is carried out in a
solvent system such as DMF and water. In another embodiment, the
R.sup.3-substitution is carried out in a solvent system such as
toluene, ethanol and water. Finally compound 9a is hydrolyzed to
the corresponding amino compound. In one embodiment, the hydrolysis
is performed using trifluoroacetic acid (TFA). In another
embodiment, the hydrolysis is carried out using HCl in dioxane.
##STR00030##
[0083] Scheme Ia provides the preparation of the compounds of the
invention where R.sup.1 is a substituted aryl or heteroaryl and
R.sup.2 is morpholine. In this scheme, compound 6a is formed as
described above in Scheme I. In one embodiment, the
R.sup.1-substituted 3-bromoaniline 1a is reacted with chloral
hydrate and NH.sub.2OH.HCl in the presence of Na.sub.2SO.sub.4 and
hydrochloric acid at 90.degree. C. to provide compound 2a. In
another embodiment, the R.sup.1-substituted 3-bromoaniline 1a is
reacted with about 1 equivalents of chloral hydrate and about 3
equivalents of NH.sub.2OH.HCl in the presence of Na.sub.2SO.sub.4
and hydrochloric acid at about 90.degree. C. to provide compound
2a. Compound 2a is then added to sulfuric acid at about 50.degree.
C., followed by a warming of the solution to about 90.degree. C.
Compound 3a is then reacted with hydrogen peroxide and 2N NaOH at
about 0.degree. C. to provide compound 4a. In one embodiment,
compound 3a is reacted with about 1.5 volumes of 30% hydrogen
peroxide and about 5 volumes of 2N NaOH at about 0.degree. C. to
provide compound 4a. Compound 4a is then reacted with urea at about
200.degree. C. to provide compound 5a. In one embodiment, compound
4a is reacted with about 10 equivalents of urea at about
200.degree. C. to provide compound 5a. Compound 5a is then reacted
with phosphoryl chloride and DIPEA at about 130.degree. C. to
provide compound 6a. Compound 6a is reacted with morpholine to
provide compound 7b. In one embodiment, the reaction is performed
at about 0.degree. C. In another embodiment, the reaction is
performed in methylene chloride at about 0.degree. C. Compound 7b
is then R.sup.3-substituted to provide compound 8b. In one
embodiment, compound 7b is R.sup.3-substituted using
R.sup.3B(OR).sub.2. In another embodiment, compound 7b is R.sup.3
substituted using R.sup.3B(OR).sub.2 and
PdCl.sub.2(PPh.sub.3).sub.2 at about 90-95.degree. C. in the
presence of Na.sub.2CO.sub.3, toluene, ethanol and H.sub.2O. In
another embodiment, compound 7b is R.sup.3-substituted using
R.sup.3B(OR).sub.2 and a catalytic amount of
PdCl.sub.2(PPh.sub.3).sub.2 at about 90-95.degree. C. in the
presence of Na.sub.2CO.sub.3, DMF and H.sub.2O to provide compound
8b. Compound 8b is then substituted with
2-((tert-butoxycarbonyl)amino)pyrimidine using
(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid to
provide compound 9b. In one embodiment, the reaction is performed
in the presence of a catalytic amount of Pd(PPh.sub.3).sub.4 and
K.sub.3PO.sub.4 at about 90-110.degree. C. In another embodiment,
the reaction is performed in the presence of about 0.05 equivalents
of PdCl.sub.2(PPh.sub.3).sub.2 and about 2 equivalents of
Cs.sub.2CO.sub.3 at about 90-95.degree. C. Finally, compound 9b is
hydrolyzed using TFA in methylene chloride of HCl in dioxane to
provide compound (I-A).
##STR00031##
[0084] Scheme Ib provides the preparation of the compounds of the
invention where R.sup.1 is F and R.sup.2 is morpholine following
the synthetic route described in Scheme I. Specifically
3-bromo-4-fluoro-aniline 1b is reacted with chloral hydrate and
hydroxylamine hydrochloride at about 90.degree. C. to provide
N-(3-bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide 2b. In one
embodiment, 3-bromo-4-fluoro-aniline 1b is reacted with about 1
equivalent of chloral hydrate and about 3 equivalents of
NH.sub.2OH.HCl in the presence of Na.sub.2SO.sub.4 and hydrochloric
acid. Addition of
N-(3-bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide 2b to sulfuric
acid at about 50.degree. C., followed by raising the temperature of
the solution to about 90.degree. C. provided
5-fluoro-6-bromo-1H-indolin-2,3-dione 3b. Conversion of
5-fluoro-6-bromo-1H-indolin-2,3-dione 3b to
3-fluoro-4-bromo-6-amino-benzoic acid 4b was performed using
hydrogen peroxide. In one embodiment, the reaction is performed at
about 0.degree. C. In another embodiment,
3-fluoro-4-bromo-6-amino-benzoic acid 4b is prepared using about
1.5 volumes of H.sub.2O.sub.2 at about 0.degree. C. in the presence
of NaOH, such as 2N NaOH. Conversion of
3-fluoro-4-bromo-6-amino-benzoic acid 4b to
6-fluoro-7-bromo-quinazolin-2,4-dione 5b may be performed using
urea at about 200.degree. C. In one embodiment,
3-fluoro-4-bromo-6-amino-benzoic acid 4b is converted to
6-fluoro-7-bromo-quinazolin-2,4-dione 5b using an excess, i.e.,
about 10 equivalents, of urea. Replacement of the oxo groups of
6-fluoro-7-bromo-quinazolin-2,4-dione 5b with chlorine groups may
be performed using a chlorinating agent such as POCl.sub.3. In one
embodiment, the reaction is performed in the presence of DIPEA at
about 130.degree. C. The resultant
2,4-dichloro-6-fluoro-7-bromo-quinazoline 6b is then reacted with
morpholine at about 0.degree. C. to provide
2-chloro-4-morpholino-6-fluoro-7-bromo-quinazoline 7c.
R.sup.3-substitution of
2-chloro-4-morpholino-6-fluoro-7-bromo-quinazoline 7c may be
performed using R.sup.3B(OR).sub.2. In one embodiment,
R.sup.3-substitution is performed in the presence of a catalytic
amount of PdCl.sub.2(PPh.sub.3).sub.2. In another embodiment, the
reaction is performed at about 90-95.degree. C. in the presence of
Na.sub.2CO.sub.3, ethanol and H.sub.2O. The 2-position of compound
8c is then substituted with a
2-(tert-butoxycarbonyl)amino)pyrimidine using
(2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid to
provide compound 9c. In one embodiment, the reaction is performed
in the presence of a catalytic amount of
PdCl.sub.2(PPh.sub.3).sub.2. In another embodiment, the reaction is
also performed in the presence of about 2 equivalents of
Cs.sub.2CO.sub.3 and DMF at about 75.degree. C. to provide compound
9c. Finally, deprotection of compound 9c is performed using TFA or
HCl, such as 4N HCl in 1,4-dioxane at about 0.degree. C. to room
temperature.
##STR00032##
[0085] Scheme II provides the preparation of compounds of the
invention where X is N. In this scheme, cyano-pyridine compound 10a
is hydrolyzed to the corresponding amide compound 11a. In one
embodiment, the hydrolysis is performed as a hydrogenolysis using
hydrogen gas and a suitable catalyst in ethanol. In another
embodiment, the hydrolysis is performed using hydrogen and Raney
nickel in ethanol. Amide compound 11a is then converted to the
corresponding acid compound 12a using reagents known to those
skilled in the art. In one embodiment, compound 11a is reacted with
a base such as aqueous sodium hydroxide. In another embodiment,
compound 11a is reacted with aqueous sodium hydroxide at elevated
temperatures such as 120.degree. C. In a further embodiment,
compound 11a is reacted with an excess, i.e., about 5 equivalents,
of sodium hydroxide in water. Compound 12a is then reacted with
urea to form compound 13a. In one embodiment, an excess, i.e.,
about 5 equivalents, of urea is utilized. In another embodiment,
compound 12a is reacted with urea at elevated temperatures, e.g.,
about 200.degree. C. The 2 and 4-positions of compound 13a are then
chlorinated using a chlorinating agent to provide compound 14a. In
one embodiment, the chlorinating agent is phosphoryl chloride. In
another embodiment, compound 13a is reacted with phosphoryl
chloride in the presence of DIPEA at elevated temperatures, e.g.,
130.degree. C. Compound 14a is then substituted at the 4-position
with R.sup.2, i.e., an optionally substituted morpholine
substituent, to provide compound 15a. In one embodiment, compound
14a is reacted with an optionally substituted morpholine reagent to
provide compound 15a. In another embodiment, the reaction is
performed at reduced temperatures, e.g., about 0.degree. C., for
about 15-30 minutes. Compound 15a is then R.sup.3-substituted at
the 7-position to provide compound 16a. In one embodiment, the
R.sup.3-substitution is performed using R.sup.3B(OH).sub.2 or
R.sup.3B(OR).sub.2. In another embodiment, the R.sup.3-substitution
is performed in the presence of a catalyst such as
PdCl.sub.2(PPh.sub.3).sub.2 in the presence of Na.sub.2CO.sub.3
(2.0 eq), in a solvent system such as toluene, ethanol and
H.sub.2O, or DMF and H.sub.2O. In yet another embodiment, the
R.sup.3-substitution is performed at elevated temperatures, such as
about 90.degree. C. to about 95.degree. C. Compound 16a is then
substituted at the 2-position with a pyrimidine substituent to
provide compound 17a. In one embodiment, compound 16a is reacted
with (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid. In
another embodiment, the reaction is performed in the presence of a
catalyst such as Pd(PPh.sub.3).sub.4 or PdCl.sub.2(PPh.sub.3).sub.2
in the presence of K.sub.3PO.sub.4 or Cs.sub.2CO.sub.3, in a
solvent system such as DMF and H.sub.2O, or
toluene/ethanol/H.sub.2O. In a yet another embodiment, the reaction
is performed at about 90.degree. C. to about 110.degree. C. In
still a further embodiment, the reaction is performed at about
90.degree. C. to about 95.degree. C. or about 90.degree. C. to
about 110.degree. C. Finally, the BOC group of compound 17a is
removed to provide compound (I-C). In one embodiment, the BOC group
is removed using TFA or HCl. In another embodiment, the BOC group
is removed by using TFA in DCM at about 0.degree. C. to about room
temperature.
##STR00033##
[0086] Scheme IIa provides the preparation of compounds (I-D),
where X is N, R.sup.2 is morpholine, and compound 14a is prepared
as described in Scheme II. Compound 14a is then substituted at the
4-position with a morpholine substituent by its reaction with
morpholine to provide compound 15b. In one embodiment, the reaction
is performed at reduced temperatures, e.g., about 0.degree. C.
Compound 15b is then R.sup.3-substituted at the 7-position to
provide compound 16b. In one embodiment, the R.sup.3-substitution
is performed using R.sup.3B(OR).sub.2. In another embodiment, the
R.sup.3-substitution is performed in the presence of a catalyst,
such as PdCl.sub.2(PPh.sub.3).sub.2 in the presence of
Na.sub.2CO.sub.3 (2.0 eq), in a solvent system such as toluene,
ethanol and H.sub.2O, or DMF and H.sub.2O. In yet another
embodiment, the R.sup.3-substitution is performed at elevated
temperatures, such as about 90.degree. C. to about 95.degree. C.
Compound 16b is then substituted at the 2-position with a
pyrimidine substituent to provide compound 17b. In one embodiment,
compound 16b is reacted with
(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid. In
another embodiment, the reaction is performed in the presence of a
catalyst such as Pd(PPh.sub.3).sub.4 or PdCl.sub.2(PPh.sub.3).sub.2
in the presence of K.sub.3PO.sub.4 or Cs.sub.2CO.sub.3, in a
solvent system such as DMF and H.sub.2O, or
toluene/ethanol/H.sub.2O. In a yet another embodiment, the reaction
is performed at about 90 to about 110.degree. C. In still a further
embodiment, the reaction is performed at about 90.degree. C. to
about 95.degree. C. Finally, the BOC group of compound 17b is
removed to provide compound (I-C). In one embodiment, the BOC group
is removed using TFA or HCl. In another embodiment, the BOC group
is removed by using TFA in DCM at about 0.degree. C. to about room
temperature.
##STR00034##
[0087] Scheme III provides the preparation of compounds (I-E) and
(I-F), which are encompassed by the compounds of formula (I). In
one embodiment, R.sup.3 is F or CH.sub.3. In another embodiment,
R.sup.9 is an optionally substituted alkyl, cycloalkyl, aryl, or
heteroaryl. Specifically, compound 7a may be prepared as described
in Scheme I and compound 15a may be prepared as described in Scheme
II. Compound 7a or 15a is then converted to carboxylic acid
compounds 21a or 22a, respectively. In one embodiment, compound 7a
or 15a is reacted with an optionally substituted carboxyphenyl
boronic acid or carboxyphenylboronic acid pinacol ester to provide
compound 21a or 22a, respectively. In another embodiment, the
reaction is performed in the presence of a catalytic amount of
PdCl.sub.2(PPh.sub.3).sub.2 in the presence of Na.sub.2CO.sub.3, in
a solvent system such as toluene, ethanol and H.sub.2O, or DMF and
H.sub.2O. In yet another embodiment, the reaction is performed at
elevated temperatures, such as about 95.degree. C. Carboxylic acid
compounds 21a and 22a are then converted to the corresponding amide
compounds 23a and 24a, respectively. In one embodiment, compound
21a or 22a is reacted with an amine such as NH.sub.2R.sup.9. In
another embodiment, the reaction is performed in DMF in the
presence of HATU and TEA. In still another embodiment, the reaction
is performed at about room temperature. Compounds 23a and 24a are
then substituted at the 2-position with a pyrimidine substituent to
provide compound 25a and 26a, respectively. In one embodiment, the
reaction is performed with an amine protected pyrimidine boronic
acid such as (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic
acid. In another embodiment, the reaction is performed in the
presence of a catalyst. In a further embodiment, the reaction is
performed in the presence of a catalytic amount of
Pd(PPh.sub.3).sub.4 or PdCl.sub.2(PPh.sub.3).sub.2 in the presence
of K.sub.3PO.sub.4 or Cs.sub.2CO.sub.3, in a solvent system such as
DMF and H.sub.2O, or toluene/ethanol/H.sub.2O. In still a further
embodiment, the reaction is performed at elevated temperatures,
such as about 90 to about 110.degree. C. Finally, compounds 26a and
27a are converted to compounds (I-E) and (I-F), respectively. In
one embodiment, compounds 26a and 27a are reacted with TFA or HCl.
In another embodiment, the reaction is performed by using TFA in
methylene chloride at about room temperature.
##STR00035##
[0088] Scheme IIIa provides the preparation of compounds (I-G) and
(I-H), which are encompassed by the compounds of formula (I). In
one embodiment, R.sup.3 is F or CH.sub.3. In another embodiment,
R.sup.9 is an optionally substituted alkyl, cycloalkyl, aryl, or
heteroaryl. Specifically, compound 7b may be prepared as described
in Scheme Ia and compound 15b may be prepared as described in
Scheme IIa. Compound 7b or 15b is then converted to carboxylic acid
compounds 21b or 22b, respectively. In one embodiment, compound 7b
or 15b is reacted with an optionally substituted carboxyphenyl
boronic acid or carboxyphenylboronic acid pinacol ester to provide
compound 21b or 22b, respectively. In another embodiment, the
reaction is performed in the presence of a catalytic amount of
PdCl.sub.2(PPh.sub.3).sub.2 in the presence of Na.sub.2CO.sub.3, in
a solvent system such as toluene, ethanol and H.sub.2O, or DMF and
H.sub.2O. In yet another embodiment, the reaction is performed at
elevated temperatures, such as about 95.degree. C. Carboxylic acid
compound 21b or 22b is then converted to the corresponding amide
compound 23b and 24b, respectively. In one embodiment, compound 21b
or 22b is reacted with an amine such as NH.sub.2R.sup.9. In another
embodiment, the reaction is performed in DMF in the presence of
HATU and TEA. In still another embodiment, the reaction is
performed at about room temperature. Compound 23b or 24b is then
substituted at the 2-position with a pyrimidine substituent to
provide compound 25b or 26b, respectively. In one embodiment, the
reaction is performed with an amine protected pyrimidine boronic
acid such as (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic
acid. In another embodiment, the reaction is performed in the
presence of a catalyst. In a further embodiment, the reaction is
performed in the presence of a catalytic amount of
Pd(PPh.sub.3).sub.4 or PdCl.sub.2(PPh.sub.3).sub.2 in the presence
of K.sub.3PO.sub.4 or Cs.sub.2CO.sub.3, in a solvent system such as
DMF and H.sub.2O, or toluene/ethanol/H.sub.2O. In still a further
embodiment, the reaction is performed at elevated temperatures,
such as about 90 to about 110.degree. C. Finally, compound 26b or
27b are converted to compound (I-E) or (I-F), respectively. In one
embodiment, compound 26a or 27a is reacted with TFA or HCl. In
another embodiment, the reaction is performed by using TFA in
methylene chloride at about room temperature.
##STR00036##
[0089] Scheme IIIb provides the preparation of compounds
encompassed by formula (I) where R.sup.1 is an amide-substituted
heteroaryl. In this scheme, compound 15c is reacted with
5-formyl-2-furanylboronic acid to provide
5-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carba-
ldehyde. In one embodiment, the reaction is performed in the
presence of a catalyst such as PdCl.sub.2(Ph).sub.3 in the presence
of Na.sub.2CO.sub.3, in a solvent system such as toluene, ethanol
and H.sub.2O, or DMF and H.sub.2O. In another embodiment, the
reaction is performed at about 90 to about 95.degree. C. The
aldehyde substituent of
5-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carbaldehyde
is then converted to the carboxylate thereby providing methyl
5-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carboxylate.
In one embodiment, this conversion is performed using NaCN and
MnO.sub.2. In one embodiment, the conversion is performed in
methanol at about 0.degree. C. The 2-position of methyl
5-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carboxylate
is then substituted with an amine-protected pyrimidine substituent
to provide
5-(2-(2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)-4-morpholinopy-
rido[3,2-d]pyrimidin-7-yl)furan-2-carboxylic acid. In one
embodiment, methyl
5-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carbox-
ylate is reacted with
(2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid. In
another embodiment, this reaction is performed in the presence of a
catalytic amount of Pd(PPh.sub.3).sub.4 or
PdCl.sub.2(PPh.sub.3).sub.2 in the presence of K.sub.3PO.sub.4 or
Cs.sub.2CO.sub.3, in a solvent system such as DMF and H.sub.2O, or
toluene/ethanol/H.sub.2O. In a further embodiment, the reaction is
performed at elevated temperatures such as about 90.degree. C. to
about 95.degree. C. The ester group of
5-(2-(2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)-4-morpholinopyrido[3,2-
-d]pyrimidin-7-yl)furan-2-carboxylic acid is the converted to the
corresponding acid thereby providing
5-(2-(2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)-4-morpholinopyrido[3,2-
-d]pyrimidin-7-yl)furan-2-carboxylic acid. In one embodiment, the
reaction is performed using lithium hydroxide in aqueous methanol
and THF. In another embodiment, the reaction is performed at about
room temperature.
5-(2-(2-(Tert-butoxycarbonyl)amino)pyrimidin-5-yl)-4-morpholinopyrido[3,2-
-d]pyrimidin-7-yl)furan-2-carboxylic acid is then reacted with an
optionally substituted amine to provide compound 27c. In one
embodiment, the amine is NHR.sup.aR.sup.b, wherein R.sup.a and
R.sup.b are, independently, CH.sub.3, C(O)(optionally substituted
heterocycle), or C(O)NH(optionally substituted heteroaryl). In
another embodiment, the reaction is performed in DMF in the
presence of HATU and TEA. Finally, the amine substituent on the
pyrimidine moiety of compound 27c is deprotected to provide
compound (I-J). In one embodiment, the deprotection is performed
using trifluoroacetic acid. In another embodiment, the deprotection
is performed in DCM at about room temperature.
##STR00037##
[0090] It will be recognized by those skilled in the art that
various additional compounds of Formula (I) can be prepared by
well-known methods, e.g., by derivatization of the amino moiety in
compound 30a or compound 31a in Scheme IV. For example, Scheme IV
provides the synthesis of compounds (I-K) to (I-N) via compound 7a
(prepared as described in Scheme I) or compound 15a (prepared as
described in Scheme II). Specifically, compound 7a or compound 15a
is reacted with an amino(optionally-substituted phenyl)boronic acid
or an amino(optionally-substituted phenyl)boronic pinacol ester to
form the corresponding compounds 28a and 29a, respectively. In one
embodiment, the compound 7a or 15a is reacted with
H.sub.2N(R.sup.8-substituted phenyl)B(OH).sub.2 or its pinacol
ester thereof. In another embodiment, the reaction is performed in
the presence of a catalyst. In a further embodiment, the reaction
is performed in the presence of a palladium catalyst such as
PdCl.sub.2(PPh.sub.3).sub.2 in the presence of Na.sub.2CO.sub.3, in
a solvent system such as toluene, ethanol and H.sub.2O, or DMF and
H.sub.2O. In yet another embodiment, the reaction is performed at
elevated temperatures such as about 90.degree. C. to about
95.degree. C. The 2-position of compound 28a or 29a is then
substituted with an amino-protected pyrimidine group to provide
compound 30a or 31a, respectively. In one embodiment compound 28a
or 29a is reacted with
(2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid. In a
further embodiment, the reaction is performed in the presence of a
catalyst. In another embodiment, the reaction is performed in the
presence of a palladium catalyst such as Pd(PPh.sub.3).sub.4 or
PdCl.sub.2(PPh.sub.3).sub.2 in the presence of K.sub.3PO.sub.4 or
Cs.sub.2CO.sub.3, in a solvent system such as DMF and H.sub.2O, or
toluene/ethanol/H.sub.2O. In still a further embodiment, the
reaction is performed at elevated temperatures such as about
90.degree. C. to about 95.degree. C. or about 90.degree. C. to
about 110.degree. C.
[0091] Compound 30a or 31a may then be converted to compounds
encompassed by formula (I). In one embodiment, compound 30a or 31a
may then be converted to compound (I-K) by reaction with an
optionally substituted carboxylic acid or an optionally substituted
carboxylic acid chloride as the first step to form the
corresponding amide intermediate compound. In one embodiment,
compound 30a or 31a is reacted with an optionally substituted
carboxylic acid such as (C.sub.1 to C.sub.6 alkyl)C(O)OH or
(C.sub.1 to C.sub.6 hydroxyalkyl)C(O)OH. In another embodiment, the
reaction is performed in DMF in the presence of HATU and TEA. In a
further embodiment, the optionally substituted carboxylic acid is
HOC(CH.sub.3).sub.2C(O)OH. In another embodiment, compound 30a is
reacted with an optionally substituted carboxylic acid chloride
such as (C.sub.1 to C.sub.6 alkyl)C(O)Cl in the presence of
pyridine or TEA. The BOC group of the pyrimidine substituent is
then removed using reagents and conditions known to those skilled
in the art. In one embodiment, the BOC-deprotection is performed
using trifluoroacetic acid. In another embodiment, the deprotection
is performed in DCM at about room temperature.
[0092] Compound 30a may also be converted to compound (I-L) via
reaction with an optionally substituted sulfonyl chloride. In one
embodiment, the sulfonyl chloride is (optionally-substituted
phenyl)SO.sub.2Cl, (optionally-substituted heteroaryl)SO.sub.2Cl,
(optionally-substituted heterocycle)SO.sub.2Cl, or
(optionally-substituted alkyl)SO.sub.2Cl. In one embodiment, the
sulfonyl chloride is selected from among the following, wherein
R.sup.6-R.sup.8, Z.sup.1, Z.sup.2, m, n, and q are defined
above:
##STR00038##
In another embodiment, the reaction with the optionally substituted
sulfonyl chloride is carried out in pyridine. The BOC group of the
pyrimidine substituent is then removed using reagents and
conditions known to those skilled in the art. In one embodiment,
the BOC group is removed using TFA. In another embodiment, the
deprotection is performed in DCM at about room temperature.
[0093] Compound 30a or 31a may also be converted to compound (I-M)
via reaction with chloroacetyl chloride to provide the following
intermediate:
##STR00039##
In one embodiment, the reaction is performed in DCM in the
presences of TEA. In another embodiment, the reaction is performed
at about 10.degree. C. to about room temperature. This chloroacetyl
intermediate is then reacted with an optionally substituted amine,
for example in DMF in the presence of potassium carbonate at
0.degree. C. to about room temperature. In one embodiment, the
optionally substituted amine is a primary amine. In another
embodiment, the optionally substituted amine is a secondary amine.
In a further embodiment, the optionally substituted amine is an
optionally substituted piperidine. In still another embodiment, the
optionally substituted amine is 4-hydroxy-piperidine. The BOC group
of the pyrimidine substituent is then removed using reagents and
conditions known to those skilled in the art. In one embodiment,
the BOC group is removed using TFA. In another embodiment, the
deprotection is performed in DCM at about room temperature.
[0094] As yet another example of the derivatization of the amino
moiety in compound 30a or compound 31a in Scheme IV to prepare
additional compounds of Formula (I), compound 30a or 31a may be
converted to compound (I-N) by their initial reaction with
2,2,2,-trichloroethyl chloroformate to form the following
intermediate:
##STR00040##
This O-(2,2,2,-trichloroethyl)carbamoyl intermediate is then
reacted with an optionally substituted amine, for example in
toluene in the presence of TEA at room temperature to about
110.degree. C. In one embodiment, the optionally substituted amine
is a primary amine. In another embodiment, the optionally
substituted amine is a secondary amine 1n a further embodiment, the
optionally substituted amine is an optionally substituted
piperidine. In still another embodiment, the optionally substituted
amine is morpholine. The BOC group of the pyrimidine substituent is
then removed using reagents and conditions known to those skilled
in the art. In one embodiment, the BOC group is removed using TFA.
In another embodiment, the deprotection is performed in DCM at
about room temperature.
##STR00041##
[0095] Scheme V provides the preparation of compounds of formula
(I-O) from starting material compound 7a. In this Scheme compound
7a, which may be prepared as described in Schemes I-III, is reacted
with an alkyl lithium reagent and DMF to provide aldehyde compound
35a. In one embodiment, the alkyl lithium reagent is n-butyl
lithium. Desirably, the reaction is performed in an ether solvent
such as THF at reduced temperatures such as about -78.degree. C. to
about room temperature. Compound 35a is then reacted with an
optionally substituted amine in the presence of trimethyl
orthoformate and a reducing agent such as sodium
triacetoxyborohydride to provide compound 36a. In one embodiment,
the optionally substituted amine is a primary amine. In another
embodiment, the optionally substituted amine is a secondary amine
1n a further embodiment, the optionally substituted amine is an
optionally substituted piperidine. In yet another embodiment, the
optionally substituted amine is an optionally substituted
piperazine. In still a further embodiment, the optionally
substituted amine has the following structure, wherein Y and
R.sup.7 are defined above:
##STR00042##
In one embodiment, Y is H,
##STR00043##
The reaction is performed in the presence of a reducing agent which
may be selected by one skilled in the art and may include sodium
triacetoxyborohydride, among others. In one embodiment, the
reaction is performed in DCE as solvent at about room
temperature.
[0096] The 2-position of compound 36a is then substituted with a
tert-butoxycarbonyl)amino-pyrimidine group to provide compound 37a.
In one embodiment, the 2-position of compound 36a is substituted
using 2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid. In
another embodiment, the substitution is performed in the presence
of a palladium catalyst such as PdCl.sub.2(PPh.sub.3).sub.2. In a
further embodiment, the pyrimidine substitution is performed at
elevated temperatures of about 90 to about 95.degree. C. In still
another embodiment, the pyrimidine substitution is performed using
Pd(PPh.sub.3).sub.4 in the presence of K.sub.3PO.sub.4. In yet a
further embodiment, the pyrimidine substitution is performed using
PdCl.sub.2(PPh.sub.3).sub.2 in the presence of Cs.sub.2CO.sub.3. In
another embodiment, the reaction is carried out in a solvent system
such as DMF and H.sub.2O, or toluene/ethanol/H.sub.2O. Finally
compound 37a is N--BOC-deprotected to the corresponding amino
compound. In one embodiment, the BOC-deprotection is performed
using an acid such as TFA or HCl in DCM or 1,4-dioxane as
solvent.
##STR00044##
[0097] Scheme Va provides the preparation of compounds of formula
(I-P) from starting material compound 7a. In this scheme, compounds
7a are prepared as described in Schemes I-III and V. Compound 35a
is then reacted with an amine having the following structure,
wherein Y and R.sup.7 are defined above, to provide compound
36b.
##STR00045##
[0098] In one embodiment, Y is H,
##STR00046##
The reaction is performed in the presence of a reducing agent which
may be selected by one skilled in the art and may include sodium
triacetoxyborohydride, among others. The 2-position of compound 36b
is then substituted with a tert-butoxycarbonyl)amino-pyrimidine
group to provide compound 37b. In one embodiment, the 2-position of
compound 36b is substituted using
2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid. In
another embodiment, the substitution is performed in the presence
of a palladium catalyst such as PdCl.sub.2(PPh.sub.3).sub.2. In a
further embodiment, the pyrimidine substitution is performed at
elevated temperatures of about 90 to about 95.degree. C. In still
another embodiment, the pyrimidine substitution is performed using
Pd(PPh.sub.3).sub.4 in the presence of K.sub.3PO.sub.4. In yet a
further embodiment, the pyrimidine substitution is performed using
PdCl.sub.2(PPh.sub.3).sub.2 in the presence of Cs.sub.2CO.sub.3.
Finally compound 37b is N--BOC-deprotected to provide the
corresponding amino compound. In one embodiment, the
BOC-deprotection is performed using an acid such as TFA or HCl in
DCM or 1,4-dioxane as solvent.
##STR00047##
[0099] Prodrugs of compounds of formula (I) may also be prepared as
described above. For example, Scheme VI describes the preparation
of prodrugs of formula (I). In one embodiment, prodrugs of formula
(I) may be prepared using the procedures of Alexander, J. Med.
Chem., 34:78-81 (1991) and International Patent Publication No.
WO-2005/028473, which are hereby incorporated by reference. In
another embodiment, prodrugs of formula (I), wherein R.sup.1 is an
amino substituted or amino terminated group, may be prepared. In
this scheme, R.sup.1 is R.sup.1'--NH.sub.2, where R.sup.1' is a
moiety derived from any of the R1 groups. Compound 38a is first
reacted with a chloroalkyl chloroformate. In one embodiment, the
chloroalkyl chloroformate is ClC(O)OCH(R')Cl, where R' is H or
C.sub.1 to C.sub.6 alkyl, to provide compound 39a. In a further
embodiment, R' is H or CH.sub.3. In another embodiment, the
chloroalkyl chloroformate is chloromethylchloroformate. The
reaction is desirably performed in the presence of a strongly basic
amine such as 1,8-bis(dimethylamino)naphthalene, at a reaction
temperature of about 0.degree. C. to room temperature. The terminal
chloro group of compound 39a is then replaced with an acetate group
to provide compound 40a. In one embodiment, the replacement is
performed using mercuric acetate and acetic acid. In another
embodiment, the replacement is performed using an excess of
mercuric acetate. The nitrogen atom of the amide group of compound
40a is then substituted to form the corresponding acyl substituent
in compound 41a. In one embodiment, the nitrogen atom of the amide
group of compound 40a is substituted with a C(O)R'' group, wherein
R'' is C.sub.1 to C.sub.6 alkyl or C.sub.3 to C.sub.8 cycloalkyl.
In another embodiment, R'' is CH.sub.3 or cyclopropyl. In a further
embodiment, compound 40a is reacted with acetic anhydride.
Desirably, the reaction is performed in the presence of a base such
as triethylamine and a catalyst such as
N,N-dimethylpyridin-4-amine. The chloro group at the 2-position of
compound 41a is then replaced with a 2-amino-pyrimidine group to
provide compound 50a, i.e., a prodrug of a compound of formula (I).
In one embodiment, compound 41a is reacted with
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine.
In another embodiment, compound 41a is reacted with
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine in
the presence of potassium phosphate tribasic and a catalyst such as
Pd(PPh.sub.3).sub.4 at a temperature of about 80.degree. C.
##STR00048##
[0100] Scheme VIa also provides a route to prodrugs of formula (I)
as described in Scheme VI where R.sup.1 is an amino-substituted
phenyl group. In one embodiment, R.sup.1 is a 3-aniline group. In
another embodiment, R.sup.1 is a 4-aniline group. Specifically,
Compound 38b is reacted with a chloroalkyl chloroformate in the
presence of a strongly basic amine such as
1,8-bis(dimethylamino)naphthalene, at a reaction temperature of
about 0.degree. C. to room temperature. In one embodiment, the
chloroalkyl chloroformate is ClC(O)OCH(R')Cl, where R' is H or
C.sub.1 to C.sub.6 alkyl, to provide compound 39b. In a further
embodiment, R' is H or CH.sub.3. In another embodiment, the
chloroalkyl chloroformate is chloromethylchloroformate. The
terminal chloro group of compound 39b is then replaced with an
acetate group to provide compound 40b. In one embodiment, the
replacement is performed using mercuric acetate and acetic acid.
The nitrogen atom of the amide group of compound 40b is then
substituted to form the corresponding acyl substituent in compound
41b. In one embodiment, the nitrogen atom of the amide group of
compound 40b is substituted with a C(O)R'' group, wherein R'' is
C.sub.1 to C.sub.6 alkyl or C.sub.3 to C.sub.8 cycloalkyl, in the
presence of a base such as triethylamine and a catalyst such as
N,N-dimethylpyridin-4-amine. In another embodiment, R'' is CH.sub.3
or cyclopropyl. In a further embodiment, compound 40b is reacted
with acetic anhydride. The chloro group at the 2-position of
compound 41b is then replaced with a 2-amino-pyrimidine group to
provide compound 50b, i.e., a prodrug of a compound of formula (I).
In one embodiment, compound 41b is reacted with
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine 1n
another embodiment, compound 41b is reacted with
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine in
the presence of potassium phosphate tribasic and a catalyst such as
Pd(PPh.sub.3).sub.4.
[0101] Pharmaceutical compositions useful herein contain a compound
of formula (I) in a pharmaceutically acceptable carrier optionally
with other pharmaceutically inert or inactive ingredients. In
another embodiment, a compound of formula (I) is present in a
single composition. In a further embodiment, a compound of formula
(I) is combined with one or more excipients and/or other
therapeutic agents as described below.
[0102] The pharmaceutical compositions of the invention comprise an
amount of a compound of formula (I) or a pharmaceutically
acceptable salt, solvate, or prodrug thereof that is effective for
regulating the PI3K/AKT/mTOR pathway in a subject. Specifically,
the dosage of the compound of formula (I) to achieve a therapeutic
effect will depend on the formulation, age, weight and sex of the
patient and route of delivery. It is also contemplated that the
treatment and dosage of the compound of formula (I) may be
administered in unit dosage form and that one skilled in the art
would adjust the unit dosage form accordingly to reflect the
relative level of activity. The decision as to the particular
dosage to be employed (and the number of times to be administered
per day) is within the discretion of the ordinarily-skilled
physician, and may be varied by titration of the dosage to the
particular circumstances to produce the desired therapeutic effect.
In one embodiment, the therapeutically effective amount is about
0.01 mg/kg to 10 mg/kg body weight. In another embodiment, the
therapeutically effective amount is less than about 5 g/kg, about
500 mg/kg, about 400 mg/kg, about 300 mg/kg, about 200 mg/kg, about
100 mg/kg, about 50 mg/kg, about 25 mg/kg, about 10 mg/kg, about 1
mg/kg, about 0.5 mg/kg, about 0.25 mg/kg, about 0.1 mg/kg, about
100 .mu.g/kg, about 75 .mu.g/kg, about 50 .mu.g/kg, about 25
.mu.g/kg, about 10 .mu.g/kg, or about 1 .mu.g/kg. However, the
therapeutically effective amount of the compound of formula (I) can
be determined by the attending physician and depends on the
condition treated, the compound administered, the route of
delivery, the age, weight, severity of the patient's symptoms and
response pattern of the patient.
[0103] The therapeutically effective amounts may be provided on
regular schedule, i.e., daily, weekly, monthly, or yearly basis or
on an irregular schedule with varying administration days, weeks,
months, etc. Alternatively, the therapeutically effective amount to
be administered may vary. In one embodiment, the therapeutically
effective amount for the first dose is higher than the
therapeutically effective amount for one or more of the subsequent
doses. In another embodiment, the therapeutically effective amount
for the first dose is lower than the therapeutically effective
amount for one or more of the subsequent doses. Equivalent dosages
may be administered over various time periods including, but not
limited to, about every 2 hours, about every 6 hours, about every 8
hours, about every 12 hours, about every 24 hours, about every 36
hours, about every 48 hours, about every 72 hours, about every
week, about every two weeks, about every three weeks, about every
month, and about every two months. The number and frequency of
dosages corresponding to a completed course of therapy will be
determined according to the judgment of a health-care practitioner.
The therapeutically effective amounts described herein refer to
total amounts administered for a given time period; that is, if
more than one compound of formula (I) or a pharmaceutically
acceptable salt or prodrug thereof is administered, the
therapeutically effective amounts correspond to the total amount
administered.
[0104] The pharmaceutical compositions containing a compound of
formula (I) may be formulated neat or with one or more
pharmaceutical carriers for administration. The amount of the
pharmaceutical carrier(s) is determined by the solubility and
chemical nature of the compound of formula (I), chosen route of
administration and standard pharmacological practice. The
pharmaceutical carrier(s) may be solid or liquid and may
incorporate both solid and liquid carriers. A variety of suitable
liquid carriers are known and may be readily selected by one of
skill in the art. Such carriers may include, e.g.,
dimethylsulfoxide (DMSO), saline, buffered saline,
hydroxypropylcyclodextrin, and mixtures thereof. Similarly, a
variety of solid carriers and excipients are known to those of
skill in the art. The compounds of formula (I) may be administered
by any route, taking into consideration the specific condition for
which it has been selected. The compounds of formula (I) may, be
delivered orally, by injection, inhalation (including orally,
intranasally and intratracheally), ocularly, transdermally,
intravascularly, subcutaneously, intramuscularly, sublingually,
intracranially, epidurally, rectally, and vaginally, among
others.
[0105] Although the compound of formula (I) may be administered
alone, it may also be administered in the presence of one or more
active pharmaceutical ingredient that are physiologically
compatible. The carriers may be in dry or liquid form and must be
pharmaceutically acceptable. Liquid pharmaceutical compositions are
typically sterile solutions or suspensions. When liquid carriers
are utilized for parenteral administration, they are desirably
sterile liquids. Liquid carriers are typically utilized in
preparing solutions, suspensions, emulsions, syrups and elixirs. In
one embodiment, the compound of formula (I) is dissolved a liquid
carrier. In another embodiment, the compound of formula (I) is
suspended in a liquid carrier. One of skill in the art of
formulations would be able to select a suitable liquid carrier,
depending on the route of administration. The compound of formula
(I) may alternatively be formulated in a solid carrier. In one
embodiment, the composition may be compacted into a unit dose form,
i.e., tablet or caplet. In another embodiment, the composition may
be added to unit dose form, i.e., a capsule. In a further
embodiment, the composition may be formulated for administration as
a powder. The solid carrier may perform a variety of functions,
i.e., may perform the functions of two or more of the excipients
described below. For example, solid carrier may also act as a
flavoring agent, lubricant, solubilizer, suspending agent, filler,
glidant, compression aid, binder, disintegrant, or encapsulating
material.
[0106] The composition may also be sub-divided to contain
appropriate quantities of the compound of formula (I). For example,
the unit dosage can be packaged compositions, e.g., packeted
powders, vials, ampoules, prefilled syringes or sachets containing
liquids.
[0107] Examples of excipients which may be combined with one or
more compound of formula (I) include, without limitation,
adjuvants, antioxidants, binders, buffers, coatings, coloring
agents, compression aids, diluents, disintegrants, emulsifiers,
emollients, encapsulating materials, fillers, flavoring agents,
glidants, granulating agents, lubricants, metal chelators,
osmo-regulators, pH adjustors, preservatives, solubilizers,
sorbents, stabilizers, sweeteners, surfactants, suspending agents,
syrups, thickening agents, or viscosity regulators. See, for
example, the excipients described in the "Handbook of
Pharmaceutical Excipients", 5.sup.th Edition, Eds.: Rowe, Sheskey,
and Owen, APhA Publications (Washington, D.C.), Dec. 14, 2005,
which is incorporated herein by reference.
[0108] In one embodiment, the compositions may be utilized as
inhalants. For this route of administration, compositions may be
prepared as fluid unit doses using a compound of formula (I) and a
vehicle for delivery by an atomizing spray pump or by dry powder
for insufflation.
[0109] In another embodiment, the compositions may be utilized as
aerosols, i.e., oral or intranasal. For this route of
administration, the compositions are formulated for use in a
pressurized aerosol container together with a gaseous or liquefied
propellant, e.g., dichlorodifluoromethane, carbon dioxide,
nitrogen, propane, and the like. Also provided is the delivery of a
metered dose in one or more actuations.
[0110] In another embodiment, the compositions may be administered
by a sustained delivery device. "Sustained delivery" as used herein
refers to delivery of a compound of formula (I) which is delayed or
otherwise controlled. Those of skill in the art know suitable
sustained delivery devices. For use in such sustained delivery
devices, the compound of formula (I) is formulated as described
herein.
[0111] In addition to the components described above for use in the
composition and the compound of formula (I), the compositions may
contain one or more medications or therapeutic agents which are
used to treat solid tumors. In one embodiment, the medication is a
chemotherapeutic. Examples of chemotherapeutics include those
recited in the "Physician's Desk Reference", 64.sup.th Edition,
Thomson Reuters, 2010, which is hereby incorporated by reference.
Therapeutically effective amounts of the additional medication(s)
or therapeutic agents are well known to those skilled in the art.
However, it is well within the attending physician to determine the
amount of other medication to be delivered.
[0112] The compounds of formula (I) and/or other medication(s) or
therapeutic agent(s) may be administered in a single composition.
However, the present invention is not so limited. In other
embodiments, the compounds of formula (I) may be administered in
one or more separate formulations from other compounds of formula
(I), chemotherapeutic agents, or other agents as is desired.
[0113] Also provided herein are kits or packages of pharmaceutical
formulations containing the compounds of formula (I) or
compositions described herein. The kits may be organized to
indicate a single formulation or combination of formulations to be
taken at each desired time.
[0114] Suitably, the kit contains packaging or a container with the
compound of formula (I) formulated for the desired delivery route.
Suitably, the kit contains instructions on dosing and an insert
regarding the active agent. Optionally, the kit may further contain
instructions for monitoring circulating levels of product and
materials for performing such assays including, e.g., reagents,
well plates, containers, markers or labels, and the like. Such kits
are readily packaged in a manner suitable for treatment of a
desired indication. For example, the kit may also contain
instructions for use of a spray pump or other delivery device.
Other suitable components to include in such kits will be readily
apparent to one of skill in the art, taking into consideration the
desired indication and the delivery route.
[0115] The compounds of formula (I) or compositions described
herein can be a single dose or for continuous or periodic
discontinuous administration. For continuous administration, a
package or kit can include the compound of formula (I) in each
dosage unit (e.g., solution, lotion, tablet, pill, or other unit
described above or utilized in drug delivery), and optionally
instructions for administering the doses daily, weekly, or monthly,
for a predetermined length of time or as prescribed. When the
compound of formula (I) is to be delivered periodically in a
discontinuous fashion, a package or kit can include placebos during
periods when the compound of formula (I) is not delivered. When
varying concentrations of a composition, of the components of the
composition, or the relative ratios of the compounds of formula (I)
or agents within a composition over time is desired, a package or
kit may contain a sequence of dosage units which provide the
desired variability.
[0116] A number of packages or kits are known in the art for
dispensing pharmaceutical agents for periodic oral use. In one
embodiment, the package has indicators for each period. In another
embodiment, the package is a labeled blister package, dial
dispenser package, or bottle.
[0117] The packaging means of a kit may itself be geared for
administration, such as an inhalant, syringe, pipette, eye dropper,
or other such apparatus, from which the formulation may be applied
to an affected area of the body, such as the lungs, injected into a
subject, or even applied to and mixed with the other components of
the kit.
[0118] The compositions of these kits also may be provided in dried
or lyophilized forms. When reagents or components are provided as a
dried form, reconstitution generally is by the addition of a
suitable solvent. It is envisioned that the solvent also may be
provided in another package.
[0119] The kits of the present invention also will typically
include a means for containing the vials in close confinement for
commercial sale such as, e.g., injection or blow-molded plastic
containers into which the desired vials are retained. Irrespective
of the number or type of packages and as discussed above, the kits
also may include, or be packaged with a separate instrument for
assisting with the injection/administration or placement of the
composition within the body of an animal. Such an instrument may be
an inhalant, syringe, pipette, forcep, measuring spoon, eye dropper
or any such medically approved delivery means.
[0120] In one embodiment, a kit is provided and contains a compound
of formula (I). The compound of formula (I) may be in the presence
or absence of one or more of the carriers or excipients described
above. The kit may optionally contain instructions for
administering the medication and the compound of formula (I) to a
subject having a disease characterized by the dysregulation of the
PI3K/AKT/mTOR pathway.
[0121] In a further embodiment, a kit is provided and contains a
compound of formula (I) in a second dosage unit, and one or more of
the carriers or excipients described above in a third dosage unit.
The kit may optionally contain instructions for administering the
medication and the compound of formula (I) to a subject having a
disease characterized by the dysregulation of the PI3K/AKT/mTOR
pathway.
[0122] The compounds described herein are useful in regulating
conditions which are associated with the PI3K/AKT/mTOR pathway. In
one embodiment, such a disease is associated with abnormal cellular
proliferation. The term "abnormal cellular proliferation" refers to
the uncontrolled growth of cells which are naturally present in a
mammalian body. In one embodiment, a disease which is characterized
by abnormal cellular proliferation is cancer, including, without
limitation, cancer of the prostate, head, neck, eye, mouth, throat,
esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon,
rectum, stomach, bladder, uterus, cervix, breast, ovaries, vagina,
testicles, skin, thyroid, blood, lymph nodes, kidney, liver,
intestines, pancreas, brain, central nervous system, adrenal gland,
or skin or a leukemia. In one embodiment, the disease characterized
by abnormal cellular proliferation is cancer of the prostate.
[0123] The compounds of formula (I) regulate activity of mTOR and
of PI3K. In a further embodiment, the compounds of formula (I)
regulate PI3K activity. The tested compounds of formula (I) have
the ability to inhibit all four isoforms of PI3K (.alpha., .beta.,
.delta., .gamma.) with at least two of the compounds showing
selectivity for the .alpha. PI3K isoform. These compounds
associated with selective activity for the .alpha. isoform may be
particularly well suited for treatment of conditions associated
with the PI3K isoform, including, e.g., breast and gastric cancers,
colorectal tumors, glioblastomas, and prostate cancer, and lung
cancers.
[0124] In another embodiment, the compounds of formula (I) regulate
the pathway of the PI3K-.beta. isoform. In still a further
embodiment, the compounds of formula (I) regulate the pathway of
the PI3K-.delta. isoform. In yet another embodiment, the compounds
of formula (I) regulate the pathway of the PI3K-.gamma.
isoform.
[0125] The ability of compounds to inhibit the PI3K .delta. and
PI3K .gamma. isoforms has been described with the ability to treat
acute and chronic inflammatory disorders. See, e.g., R C Camps et
al, Nat Rev Immunol., 2007, Mar. 7(3): 191-201 [PI3K delta and PI3K
gamma: partners in crime in inflammation in rheumatoid arthritis
and beyond?]. Other inflammatory disorders have been associated
more specifically with the PI3K .delta. isoform, including
neutrophil-associated inflammation. Models for testing the ability
of compounds to reduce inflammation in inflammatory arthritis are
known, e.g., as described by Camps et al, Nature Med., 2005, 11,
936-943. Camps et al (2005) also describes models useful in
assessing the ability of compounds to reduce inflammation in
peritonitis. Models for testing the ability of compounds to reduce
inflammation and/or improve healing after myocardial infarction are
described by Siragusa et al, Circ. Res. (2010), 106, 757-768. A
model for testing the ability of compounds to prevent
bleomycin-induced pulmonary fibrosis is described by Wei et al,
Biochem Biophys Res Comm. 2010, 397: 311-317 and Brent et al,
Toxicology, 2000, 147: 1-13.
[0126] The term "regulation" or variations thereof as used herein
refers to the ability of a compound of formula (I) to inhibit one
or more components of a biological pathway. In one embodiment,
"regulation" refers to inhibition of mTOR activity. In another
embodiment, "regulation" refers to inhibition of PI3K activity. In
a further embodiment, regulation refers to dual inhibition of mTOR
and PI3K activity.
[0127] The utility of the compounds of formula (I) can be
illustrated, for example, by their activity in the in vitro tumor
cell proliferation assay described below. The compounds of formula
(I) exhibit an mTOR and PI3K inhibitory activity, and therefore can
be utilized in order to inhibit abnormal cell growth in which mTOR
plays a role. Thus, the compounds of formula (I) are effective in
the treatment of disorders with which abnormal cell growth actions
of mTOR and/or PI3K dysregulation are associated, such as
cancer.
[0128] In one embodiment, methods for regulating the PI3K and/or
mTOR pathways are provided and include administering a
therapeutically effective amount of a compound of formula (I) to a
patient in need thereof.
[0129] In another desirable embodiment, methods for treating a
disease characterized by an abnormal cellular growth resulting from
a dysregulated PI3K/mTOR pathway are provided and include
administering of a therapeutically effective amount of a compound
of formula (I) to a patient in need thereof.
[0130] In a further desirable embodiment, methods for treating a
condition treatable by inhibiting the PI3K/AKT/mTOR pathway are
provided and include administering a therapeutically effective
amount of a compound of formula (I) to a patient in need
thereof.
[0131] As described herein, a therapeutically effective amount of a
compound when used for the treatment of cancer is an amount which
may reduce the number of cancer cells, reduce tumor size, inhibit
metastasis, inhibit tumor growth and/or ameliorate one or more of
the symptoms of the cancer. For cancer therapy, efficacy can be
measured for example, by assessing the time to disease progression
and/or determining the response rate.
[0132] As described herein, a therapeutically effective amount of a
compound when used for the treatment of an inflammatory disorder is
an amount which may delay the onset of or reduce the severity or
duration of an inflammatory response, or which mitigates one or
more symptoms of an inflammatory response. For treatment of an
inflammatory disorder, efficacy can be measured, for example, by a
reduction in physiologic signs of inflammation (e.g., redness,
swelling, heat, loss of function) or by measuring changes in the
levels of cells (e.g., monocytes, macrophages and other mononuclear
cells) or molecules (e.g., pro-inflammatory cytokines) associated
with inflammation.
[0133] In one aspect, the compound is of formula (I) and R.sup.2 is
morpholine. In one embodiment, R.sup.2 is morpholine substituted by
one or more methyl. In a further embodiment, R.sup.2 is:
##STR00049##
In yet another embodiment, R.sup.1 is
##STR00050##
wherein n is 1 to 5; and each R.sup.8 is independently selected
from the group consisting of halogen, alkyl, aryl, alkylsulfonyl,
alkylthio, alkylcarbonylamino, halogenated alkylcarbonylamino,
alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl,
alkylaminocarbonylamino, alkylaminoalkylcarbonylamino,
hydroxyalkylcarbonylamino, heteroarylcarbonylamino,
heteroarylalkylcarbonylamino, heteroarylcarbonyl,
heterocyclecarbonylamino, arylcarbonylamino,
alkylsulfonylheterocyclecarbonyl, heterocyclecarbonyl,
heterocycleaminocarbonyl, heteroarylalkylamino, hydroxyalkylamino,
heterocyclealkylcarbonylamino, or cyanoalkylcarbonylamino. In still
a further embodiment, the R.sup.1 substituted phenyl is 3- or
4-substituted. In another embodiment, R.sup.8 in the substituted
phenyl is selected from the group consisting of F, CH.sub.3,
C(CH.sub.3).sub.2OH, NHC(O)CH.sub.3, NHC(O)CH.sub.2CH.sub.3,
NHC(O)CH(CH.sub.3).sub.2, NHC(O)C(CH.sub.3).sub.3,
NHC(O)CH.sub.2CH.sub.2CH(CH.sub.3).sub.2, N(CH.sub.3)C(O)CH.sub.3,
NHC(O)NHCH.sub.3, NHSO.sub.2CH.sub.3,
NHC(O)CH.sub.2N(CH.sub.3).sub.2, NHC(O)C(CH.sub.3).sub.2OH,
NHC(O)CH(CH.sub.3)OH, NHC(O)CH.sub.2OH, NHC(O)CH(CH.sub.3)F,
NHC(O)C(CH.sub.3).sub.2CN, NHC(O)CH.sub.2CN, NHC(O)(cyclopropyl
optionally substituted with CN), NHC(O)cyclobutyl,
NHC(O)(cyclopentyl), NHC(O)(cyclohexyl optionally substituted with
OH), NHC(O)(adamantanyl), NHC(O)(pyridinyl), NHC(O)(furanyl
optionally substituted with CH.sub.3), NHC(O)(tetrahydropyranyl),
NHC(O)(pyrazinyl optionally substituted with CH.sub.3),
NHC(O)(piperazinyl optionally substituted with CH.sub.3),
C(O)(4-C(O)CH.sub.3-piperazinyl), NHC(O)CH.sub.2(piperazinyl
optionally substituted with CH.sub.3),
C(O)(4-SO.sub.2CH.sub.3-piperazinyl), C(O)NHCH.sub.3,
C(O)NHCH.sub.2CH.sub.2N(CH.sub.3).sub.2, C(O)N(CH.sub.3).sub.2,
C(O)NH(thiazolyl), C(O)NH(pyridinyl optionally substituted with
halogen), C(O)(piperidinyl optionally substituted with
CH.sub.2CH.sub.2OH, OH or CH.sub.3), NHC(O)(pyridinyl optionally
substituted with F or CF.sub.3), NHC(O)(thiadiazolyl),
C(O)NH(cyclopropyl), NHC(O)(phenyl optionally substituted with F),
NHSO.sub.2-(phenyl optionally substituted with F),
NHC(O)CH.sub.2(morpholinyl), NHC(O)CH.sub.2(piperidinyl optionally
substituted with OH), NHC(O)(morpholinyl), NHSO.sub.2(cyclopropyl),
piperidinyl optionally substituted with C(O)C(CH.sub.3).sub.2CN,
C(O)CH.sub.2N(CH.sub.3).sub.2, CH.sub.2CH.sub.2OH, or
C(O)C(CH.sub.3).sub.2OH, and SO.sub.2CH.sub.3. In a further
embodiment, R.sup.1 is optionally substituted heterocycle or
optionally substituted heteroaryl. In still another embodiment,
R.sup.1 is substituted with 0 to 3 R.sup.4 groups independently
selected from the group consisting of alkyl, SO.sub.2(alkyl),
alkylsulfonylamino, halogen, alkylcarbonylamino,
alkylcarbonylheterocyclecarbonyl, heterocyclecarbonyl, and
heteroarylaminocarbonyl. In yet a further embodiment, R.sup.1
is
##STR00051##
wherein Z.sup.1 is O, S, or NR.sup.5; Z.sup.2 is CR.sup.4 or N;
R.sup.4H, alkyl, C(O)(optionally substituted heterocycle), or
C(O)NH(optionally substituted heteroaryl); R.sup.5 is absent, H or
alkyl; and p is 0 to 2. In another embodiment, R.sup.1 is a
substituted heteroaryl selected from the group consisting of
pyrazole, thiophene and furan. In still a further embodiment,
R.sup.1 is a heteroaryl substituted with CH.sub.3, C(O)(optionally
substituted heterocycle), or C(O)NH(optionally substituted
heteroaryl). In another embodiment, R.sup.1 is
##STR00052##
wherein m is 0 to 4; q is 0 to 3; and each R.sup.6 is,
independently, selected from the group consisting of halogen,
piperidinyl, 4-CH.sub.3-piperidinyl, alkylsulfonyl,
aminosulfonylalkyl, and alkylcarbonylamino. In a further
embodiment, R.sup.1 is selected from among pyridine and pyrimidine.
In yet another embodiment, R.sup.1 is substituted with F, Cl,
4-CH.sub.3-piperidinyl, NHCOCH.sub.3, NHC(O)(cyclopropyl), or
SO.sub.2CH.sub.3. In still a further embodiment, R.sup.1 is an
optionally substituted benzo[b]oxazine. In yet another embodiment,
R.sup.1 is an optionally substituted benzo[b][1,3]oxazine or
benzo[b][1,4]oxazine. In a further embodiment, R.sup.1 is a
benzo[b]oxazinone. In another embodiment, R.sup.1 is an optionally
substituted benzo[b][1,3]oxazin-2-one, benzo[b][1,3]oxazin-4-one,
benzo[b][1,4]oxazin-2-one, or benzo[b][1,4]oxazin-3-one. In still a
further embodiment, R.sup.1 is optionally substituted alkyl. In yet
another embodiment, R.sup.1 is CH.sub.2-- (optionally substituted
heterocycle). In a further embodiment, R.sup.1 is CH.sub.2--
(optionally substituted piperazinyl) or CH.sub.2-(optionally
substituted piperidinyl). In still another embodiment, R.sup.1
is
##STR00053##
wherein Y and Y' are, independently, N or CH; and R.sup.7 is H,
C(O)(hydroxyalkyl), C(O)(alkyl), or NHC(O)(alkyl). In a further
embodiment, R.sup.7 is H, C(O)CH(CH.sub.3)OH,
C(O)C(CH.sub.3).sub.2OH, C(O)CH.sub.3, or NHC(O)CH.sub.3.
[0134] In another aspect, the compound is of formula (II).
[0135] In a further aspect, the compound is of formula (III). In
one embodiment, R.sup.1 is optionally substituted heteroaryl. In
another embodiment, R.sup.1 is optionally substituted phenyl. In a
further embodiment, R.sup.1 is optionally substituted heterocycle.
In still another embodiment, R.sup.1 is optionally substituted
alkyl.
[0136] In yet another aspect, the compound is of formula (IV).
[0137] In still a further aspect, the compound is of formula (I)
and R.sup.1 is optionally substituted aryl, optionally substituted
heterocycle, optionally substituted heteroaryl, or optionally
substituted alkyl;
[0138] R.sup.2 is optionally substituted morpholine or
thiomorpholine; R.sup.3 is H, F, Cl, CH.sub.3, or CH.sub.3O; X is
CH or N; or a pharmaceutically acceptable salt, prodrug or solvate
thereof.
[0139] In another aspect, the compound is of formula (I) and
R.sup.1 is optionally substituted aryl, optionally substituted
heterocycle, optionally substituted heteroaryl, or optionally
substituted alkyl; R.sup.2 is optionally substituted morpholine or
thiomorpholine; R.sup.3 is H, F, Cl, CH.sub.3, or CH.sub.3O; X is
CH or N; or a pharmaceutically acceptable salt, prodrug or solvate
thereof.
[0140] In a further aspect, any of the compounds described herein
are a salt of an acid. In one embodiment, the acid salt is selected
from among an acetic, propionic, lactic, citric, tartaric,
succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,
hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,
methanesulfonic, napthalenesulfonic, benzenesulfonic,
toluenesulfonic, trifluoroacetic, and camphorsulfonic salt.
[0141] In still another aspect, a method for co-regulating PI3K and
mTOR is provided and includes administering a therapeutically
effective amount of one or more compound described herein to a
patient in need thereof. In one embodiment, the co-regulation
includes inhibiting the PI3K/AKT/mTOR pathway.
[0142] In yet a further aspect, a method for treating a condition
treatable by inhibiting the PI3K/AKT/pathway is provided and
includes administering a therapeutically effective amount of one or
more compound described herein to a patient in need thereof.
[0143] In another aspect, a method for treating a disease
characterized by an abnormal cellular proliferation resulting from
a dysregulated PI3K/AKT/mTOR pathway is provided and includes
administering a therapeutically effective amount of one or more
compound described herein to a patient in need thereof. In one
embodiment, the disease is cancer. In another embodiment, the
disease is a cancer is of the prostate, head, neck, eye, mouth,
throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung,
colon, rectum, stomach, bladder, uterus, cervix, breast, ovaries,
vagina, testicles, skin, thyroid, blood, lymph nodes, kidney,
liver, intestines, pancreas, brain, central nervous system, adrenal
gland, or skin or a leukemia. In a further embodiment, the disease
is a cancer of the prostate. In yet another embodiment, the patient
has at least one solid tumor. In still another embodiment, the
condition is an inflammatory disorder. In yet a further embodiment,
the disease is an inflammatory disorder selected from among
arthritis, pulmonary fibrosis, myocardial infarction, and
peritonitis.
[0144] In still a further aspect, a pharmaceutical composition is
provided and contains one or more of a compound described herein
and a pharmaceutically acceptable carrier.
[0145] In another aspect, a kit is provided and includes one more
compound described herein.
[0146] The following methods outline the synthesis of the compounds
of Formula (I). The following examples are presented to illustrate
certain embodiments of the present invention, but should not be
construed as limiting the scope of this invention.
EXAMPLES
[0147] Unless otherwise stated, all the raw materials are purchased
from Sigma-Aldrich, Fluorochem, Apollo Scientific and Matrix Labs
and solvents from Ranchem, S.D. Fine and Merck labs. .sup.1H NMR
spectra were recorded on Varian 300 and 400 MHz instruments, using
TMS as internal reference. The chemical shift values are quoted in
6 (parts per million). Mass spectra of all the intermediates and
final compounds were recorded using Agilent.RTM. LC/MSD/VL and API
2000 LC/MS instruments using a Synergi.TM. 2.5.mu. MAX-RP column
(100 .ANG. Mercury; 20.times.4.0 mm), a mobile phase of 0.1% formic
acid in water and ACN, a flow rate of 2 mL/min, a temperature of
30.degree. C., and a run time of 3.0 minutes. The purity of all the
final compounds was detected using Agilent.RTM. HPLC 1100 &
1200 instruments and the following conditions: [0148] Condition 1:
Column: AG/C18/25-008 (Zorbax.RTM. Eclipse XDB-C18 column,
4.6.times.250 mm, 5.mu.), mobile phase: A=0.01% TFA in water;
B=ACN/MeOH (1:1); gradient: 95:05; flow: 1.0 mL/min; temperature:
40.degree. C.; run time: 12 min [0149] Condition 2: Column:
AG/C18/15-001 (Zorbax.RTM. Eclipse XDB-C18 column, 4.6.times.150
mm, 5.mu.), mobile phase: A=0.01% TFA in water; B=ACN/MeOH (1:1),
isocratic: 40:60, flow: 1.0 mL/min, temperature: 25.degree. C., run
time:12 min, [0150] Condition 3: Column: AG/C18/15-009 (Zorbax.RTM.
Eclipse XDB-C18 column, 4.6.times.150 mm, 5.mu.), mobile phase: A=5
mM ammonium acetate in water; B: ACN, gradient: 95:05, flow: 1.0
mL/min, temperature: 40.degree. C., run time: 12.0 min
Preparation 1: 7-Bromo-2-chloro-4-morpholin-4-yl-quinazoline
##STR00054##
[0151] Step 1: N-(3-Bromo-phenyl)-2-hydroxyimino-acetamide
##STR00055##
[0153] To a 3000 mL round bottom flask, 3-bromoaniline (50 g,
0.2907 mol), water (1500 mL), chloral hydrate (57.7 g, 0.3488 mol),
hydroxylamine hydrochloride (64.6 g, 0.9302 mol) and sodium
sulphate (250 g) were added. To this reaction mixture was slowly
added concentrated HCl (76 mL). The reaction mixture was stirred at
90.degree. C. for 2 hours. The white precipitate was formed and was
collected by filtration. The white solid was dried to provide the
title compound [60 g, 85%]. .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 12.28 (s, 1H), 10.38 (s, 1H), 8.03 (t, J=1.5 Hz, 1H),
7.62-7.65 (m, 2H), 7.29-7.31 (m, 2H). LC-MS (ESI): Calculated mass:
242.0; Observed mass [M+H].sup.+: 243.0 (RT: 0.17 min).
Step 2: 6-Bromo-1H-indole-2,3-dione
##STR00056##
[0155] To concentrated sulfuric acid (275 mL) at 50.degree. C. was
added N-(3-bromo-phenyl)-2-hydroxyimino-acetamide (55 g, 0.2272
mol). The temperature was raised to 90.degree. C. and maintained
for 3 hours. The reaction mixture was added to ice cold water to
provide a yellow precipitate. The precipitate was filtered and
dried to provide the title compound as a yellow solid (50 g, 98%).
This material was taken for next step without any further
purification.
Step 3: 2-Amino-4-bromo-benzoic acid
##STR00057##
[0157] To a 500 mL round bottom flask, 6-bromo-1H-indole-2,3-dione
(50 g, 0.2192 mol) and NaOH (20 g in 250 mL water) were added and
the reaction vessel was cooled to 0.degree. C. To this reaction
mixture, 30% hydrogen peroxide (50 mL) was slowly added. The
reaction mixture was stirred at 0.degree. C. for 2 hours. The
reaction mixture was then acidified with 2N HCl (pH 6) at 0.degree.
C. to afford the solid compound. The solid material was collected
by filtration and dried to obtain the title compound (10 g, 21%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 7.59 (d, J=8.7 Hz,
1H), 6.96 (d, J=2.1 Hz, 1H), 6.65 (dd, f=8.7 Hz, f'=1.8 Hz, 1H)
LC-MS (ESI): Calculated mass: 215.0; Observed mass [M+H].sup.+:
217.9. (RT: 0.83 min).
Step 4: 7-Bromo-1H-quinazoline-2,4-dione
##STR00058##
[0159] To a 250 mL round bottom flask, 2-amino-4-bromo-benzoic acid
(10 g, 0.0463 mol) and urea (27.78 g, 0.4629 mol) were added. The
reaction mixture was stirred at 195.degree. C. for 3 hours. The
reaction mixture was allowed to cool to 80.degree. C. and water was
added. The aqueous reaction mixture was stirred at 80.degree. C.
for 5-10 minutes then allowed to reach room temperature. The solid
was filtered, dried and azeotroped with toluene to afford the title
compound (10 g, 90%). This material was taken to the next step
without further purification.
Step 5: 7-Bromo-2,4-dichloro-quinazoline
##STR00059##
[0161] To a 250 mL round bottom flask,
7-bromo-1H-quinazoline-2,4-dione (10 g 0.0413 mol) was added. To
the same flask, POCl.sub.3 (100 mL) and DIPEA (6.5 mL, 0.0413 mol)
were added. The reaction mixture was maintained at 130.degree. C.
for 12 hours. The volatiles were evaporated and azeotroped with
toluene to provide the crude residue. The crude residue was
purified using column chromatography (60-120 silica gel, 10% ethyl
acetate in hexane) to provide the title compound (7 g, 60%).
.sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.41 (s, 1H), 8.00-8.09
(m, 1H), 7.89-7.91 (m, 1H): LC-MS (ESI): Calculated mass: 275.9;
Observed mass [M+H].sup.+: 276.8. (RT: 0.68 min).
Step 6: 7-Bromo-2-chloro-4-morpholin-4-yl-quinazoline
##STR00060##
[0163] To an ice cold solution of 7-bromo-2,4-dichloro-quinazoline
(7 g, 0.0255 mol) in dichloromethane (150 mL), morpholine (4.43 mL,
0.0509 mol) was slowly added and the reaction was continued at
0.degree. C. for 30 minutes. The solvent was evaporated to dryness
to provide the crude compound. The crude product was purified using
column chromatography (60-120 silica gel, 30% ethyl acetate in
hexane) to provide the title compound (7 g, 84%). .sup.1H NMR (300
MHz, CDCl.sub.3): .delta. 8.17 (d, J=7.5 Hz, 1H), 8.04 (d, J=7.5
Hz, 1H), 7.63 (d, J=8.1 Hz, 1H), 3.72-3.74 (m, 8H): LC-MS (ESI):
Calculated mass: 327.0; Observed mass [M+H].sup.+: 329.8. (RT: 0.45
min).
Preparation 2:
7-Bromo-2-chloro-6-fluoro-4-morpholin-4-yl-quinazoline
##STR00061##
[0164] Step 1:
N-(3-Bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide
##STR00062##
[0166] To a 500 mL round bottom flask, 3-bromo-4-fluoraniline (5 g,
0.0261 mol), water (300 mL), chloral hydrate (5.19 g, 0.0314 mol),
hydroxylamine hydrochloride (5.8 g, 0.0835 mol) and sodium sulphate
(25 g) were added. To this reaction mixture, concentrated HCl (7.5
mL) was slowly added. The reaction mixture was stirred at
90.degree. C. for 3 hours. A precipitate formed and was collected
by filtration. The solid was dried to provide the title compound
(4.2 g, 61%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 12.28
(s, 1H), 10.51 (s, 1H), 8.12 (dd, J=2.4 Hz, J=2.7 Hz, 1H), 7.68 (m,
2H), 7.36 (t, J=8.7 Hz, 1H).
Step 2: 6-Bromo-5-fluoro-1H-indole-2,3-dione
##STR00063##
[0168] To concentrated sulfuric acid (40 mL) at 50.degree. C. was
added N-(3-bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide (4 g,
0.0152 mol). The temperature was raised to 90.degree. C. and
maintained for 3 hours. The reaction mixture was added to ice cold
water to provide a precipitate. The precipitate was filtered and
dried to provide the title compound (3.0 g, 80%).
Step 3: 2-Amino-4-bromo-5-fluoro-benzoic acid
##STR00064##
[0170] To a 100 mL round bottom flask,
6-bromo-5-fluoro-1H-indole-2,3-dione (3 g, 0.0121 mol) and 2N NaOH
(15 mL) were added and cooled the reaction vessel to 0.degree. C.
To this reaction mixture, 30% hydrogen peroxide (10.5 mL) was
slowly added. The reaction mixture was stirred at 0.degree. C. for
3 hours. Subsequently, the reaction mixture was acidified with 2N
HCl at 0.degree. C. (pH 5) to afford solid compound. The solid
material was collected by filtration and dried to obtain the title
compound (700 mg, 25%). .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 7.52 (d, J=9.6 Hz, 1H), 7.09 (d, J=6.0 Hz, 1H).
Step 4: 7-Bromo-6-fluoro-1H-quinazoline-2,4-dione
##STR00065##
[0172] To a 100 mL round bottom flask,
2-amino-4-bromo-5-fluoro-benzoic acid (0.7 g, 2.99 mmol) and urea
(1.07 g, 17.94 mmol) were added. The reaction mixture was stirred
at 200.degree. C. for 2 hours. The reaction mixture was allowed to
cool to 100.degree. C. and water was added. The aqueous reaction
mixture was refluxed for 5-10 minutes and cooled to room
temperature to provide the precipitate. The solid was filtered and
dried to afford the title compound (400 mg, 51%). This material was
taken to the next step without further purification.
Step 5: 7-Bromo-2,4-dichloro-6-fluoro-quinazoline
##STR00066##
[0174] A 100 mL round bottom flask was charged with
7-bromo-6-fluoro-1H-quinazoline-2,4-dione (0.4 g 1.532 mmol). To
the same flask, POCl.sub.3 (15 mL) and DIPEA (0.714 mL, 0.005 mol)
were added. The reaction mixture was maintained at 140.degree. C.
overnight. The volatiles were evaporated and azeotroped with
toluene to provide the residue. The crude residue was purified
using column chromatography (60-120 silica gel, 20% ethyl acetate
in hexane) to provide the title compound (350 mg, 77%) This
material was immediately taken to the next step.
Step 6: 7-Bromo-2-chloro-6-fluoro-4-morpholin-4-yl-quinazoline
##STR00067##
[0176] To an ice cold solution of
7-bromo-2,4-dichloro-6-fluoro-quinazoline (0.35 g, 1.178 mmol) in
dichloromethane (15 mL), morpholine (0.566 mL, 0.0066 mol) was
slowly added and the reaction was continued for 20 minutes. The
reaction mixture was diluted with dichloromethane and washed with
water. The organic layer was dried over sodium sulphate and
evaporated to provide crude solid. The crude material was purified
using column chromatography (60-120 silica gel, 30% ethyl acetate
in hexane) to provide the title compound (220 mg, 57%). .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 8.16 (d, J=6.6 Hz, 1H), 8.01 (d,
J=9.6 Hz, 1H), 3.83-3.86 (m, 4H), 3.76-3.73 (m, 4H); LC-MS (ESI):
Calculated mass: 345.0; Observed mass [M+H].sup.+: 347.8 (RT: 1.70
min).
Preparation 3:
4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine
##STR00068##
[0177] Step 1: 3-Amino-5-bromo-pyridine-2-carboxylic acid amide
##STR00069##
[0179] To a 100 mL round bottom flask, Raney Nickel (2.5 g) and
ethanol (15 mL) were added. To the same flask, was added
5-bromo-3-nitropyridine-2-carbonitrile (5 g, 0.0219 mol). The
reaction mass was stirred under hydrogen atmosphere for 14 hours at
ambient temperature. The catalyst was removed by filtration. The
clear filtrate was evaporated to provide the crude product. The
crude material was subject to column chromatography (60-120 silica
gel, 30% ethyl acetate in hexane) to provide title compound as a
light yellow solid (1.1 g, 23%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 7.89 (br s, 1H), 7.79 (d, J=1.8 Hz, 1H),
7.40 (br s, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.04 (br s, 2H).
Step 2: 3-Amino-5-bromo-pyridine-2-carboxylic acid
##STR00070##
[0181] To a 100 mL round bottom flask,
3-amino-5-bromo-pyridine-2-carboxylic acid amide (1.05 g, 0.0049
mol) and aqueous sodium hydroxide solution (0.98 g in 10 mL water,
0.0245 mol) were added. The reaction mixture was stirred at reflux
temperature for 5 hours. The volatiles were evaporated under
reduced pressure to provide the residue. The residue was
neutralized to pH 7.0, using 2N HCl at 0.degree. C. to obtain the
precipitate. The precipitate was filtered and dried to provide the
title compound as light yellow solid (1 g, 95%). .sup.1H NMR (300
MHz, DMSO-d.sub.6): .delta. 7.65 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.1
Hz, 1H), 7.01-7.16 (br s, 2H); LC-MS (ESI): Calculated mass: 216.0;
Observed mass [M+H].sup.+: 217.0. (RT: 0.43 min).
Step 3: 7-Bromo-pyrido[2,3-d]pyrimidine-2,4-diol
##STR00071##
[0183] To a 100 mL round bottom flask,
3-amino-5-bromo-pyridine-2-carboxylic acid (1 g, 0.0046 mol) and
urea (27.8 g, 0.4629 mol) were added. The reaction mixture was
stirred at 200.degree. C. for 2.5 hours. The reaction mixture was
cooled, water was added and the mixture was stirred to provide a
precipitate. The precipitate was filtered and dried to provide the
title compound (1 g, 91%). This material was taken to the next step
without further purification.
Step 4: 7-Bromo-2,4-dichloro-pyrido[3,2-d]pyrimidine
##STR00072##
[0185] To a 100 mL round bottom flask,
7-bromo-pyrido[2,3-d]pyrimidine-2,4-diol (1 g, 0.0041 mol) was
added. To the same flask, POCl.sub.3 (10 mL) and DIPEA (1 mL) were
added. The reaction mixture was stirred at 130.degree. C. for 10
hours. The volatiles were evaporated and azeotroped with toluene
(2.times.10 mL). The obtained residue was treated with ethyl
acetate and filtered through a pad of Celite.RTM. reagent. The
filtrate was evaporated to provide the crude title compound (0.9 g,
78% crude yield). This material was taken to the next step without
further purification.
Step 5:
4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine
##STR00073##
[0187] To an ice cold solution of crude
4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (2.85 g,
0.0102 mol) in dichloromethane (25 mL) at 0.degree. C. was added
morpholine (1.8 g, 0.0204 mol). The reaction was stirred at
0.degree. C. for 30 minutes. The volatiles were evaporated and
subjected to column chromatography (60-120 silica gel, 0-12% ethyl
acetate in hexane) to provide the title compound as a light yellow
solid (0.35 g, 26%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
8.68 (d, J=2.7 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 3.86-3.89 (m, 8H):
LC-MS (ESI): Calculated mass: 328.0; Observed mass [M+H].sup.+:
330.8. (RT: 1.5 min).
Example 1
5-(7-(3-(Methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-am-
ine (Scheme I)
##STR00074##
[0188] Step 1:
4-(2-Chloro-7-(3-(methylsulfonyl)phenyl)quinazolin-4-yl)morpholine
##STR00075##
[0190] To a 50 mL round bottom flask,
4-(7-bromo-2-chloroquinazolin-4-yl)morpholine (0.25 g, 0.0007
mol--Preparation 1), 3-methylsulfonylphenylboronic acid (0.137 g,
0.0006 mol), sodium carbonate (0.121 g, 0.00105 mol), DMF (8 mL)
and water (2 mL) were added. The reaction vessel was degassed with
N.sub.2 for 5-10 minutes. To the same reaction mixture,
Pd(PPh.sub.3).sub.2Cl.sub.2 (0.027 g, 0.000035 mol) was added and
the mixture again degassed with N.sub.2 for 5-10 minutes. The
reaction mixture was stirred at 95.degree. C. for 2 hours. The
reaction mixture was cooled and water was added. The crude product
was extracted with ethyl acetate. The organic layer was washed with
water, brine and dried over sodium sulfate. The solvent was removed
under the reduced pressure to afford the crude product. The crude
product was purified by column chromatography (60-120 silica gel,
50-100% ethyl acetate in n-hexane) to provide the desired product
(0.2 g, 65%). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.25 (br
s, 1H), 8.06-7.94 (m, 3H), 7.75-7.46 (m, 3H), 3.93 (br s, 4H), 3.91
(br s, 4H), 3.12 (s, 3H): LC-MS (ESI): Calculated mass: 403.0;
Observed mass [M+H].sup.+: 404.0 (RT=1.30 min).
Step 2:
5-(7-(3-(Methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)pyrimi-
din-2-amine
##STR00076##
[0192] To a 50 mL round bottom flask,
4-(2-chloro-6-fluoro-7-(3-(methylsulfonyl)phenyl)quinazolin-4-yl)morpholi-
ne (0.06 g, 0.00015 mol), (2-aminopyrimidin-5-yl)boronic acid (0.03
g, 0.00023 mol), cesium carbonate (0.097 g, 0.0003 mol), DMF (5 mL)
and water (2 mL) were added. The reaction vessel was degassed with
N.sub.2 for 5-10 minutes. To the same reaction mixture,
Pd(PPh.sub.3).sub.2Cl.sub.2 (0.005 g, 0.0000075 mol) was added and
again degassed with N.sub.2 for 5-10 minutes. The reaction mixture
was stirred at 95.degree. C. for 2 hours. The reaction mixture was
cooled and water was added. The crude product was extracted with
ethyl acetate. The organic layer was washed with water, brine and
dried over sodium sulfate. The solvent was removed under the
reduced pressure to afford the crude product. The crude product was
purified by column chromatography (60-120 silica gel, 0-5% methanol
in chloroform) to provide the desired product (0.05 g, 7%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.22 (s, 2H), 8.36 (s, 1H),
8.25 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.01
(d, J=8.0 Hz, 1H), 7.87-7.80 (m, 2H), 7.21 (s, 2H), 3.85 (s, 8H);
.sup.1H NMR (400 MHz, DMSO-d.sub.6+D.sub.2O): .delta. 9.12 (s, 2H),
8.20 (s, 1H), 8.14-8.06 (m, 3H), 7.95 (d, J=7.6 Hz, 1H), 7.79 (t,
J=7.2 Hz, 2H), 3.83-3.77 (m, 8H), 3.21 (s, 3H). LC-MS (ESI):
Calculated mass: 462.1; Observed mass [M+H].sup.+: 463.1 (RT=0.23
min).
Example 2
5-(6-Fluoro-7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)pyrim-
idin-2-amine (Scheme 1)
##STR00077##
[0193] Step 1:
4-(2-chloro-6-fluoro-7-(3-(methylsulfonyl)-phenyl)quinazolin-4-yl)-morpho-
line
##STR00078##
[0195] To a 50 mL round bottom flask,
4-(7-bromo-2-chloro-6-fluoroquinazolin-4-yl)morpholine (0.15 g,
0.0004 mol--Preparation 2), 3-methylsulfonylphenylboronic acid
(0.078 g, 0.00039 mol), sodium carbonate (0.114 g, 0.0011 mol), DMF
(6 mL) and water (2 mL) were added. The reaction vessel was
degassed with N.sub.2 for 5-10 minutes. To the same reaction
mixture, Pd(PPh.sub.3).sub.2Cl.sub.2 (0.015 g, 0.000022 mol) was
added and again degassed with N.sub.2 for 5-10 minutes. The
reaction mixture was stirred at 90.degree. C. for 3 hours. The
reaction mixture was cooled and diluted with ethyl acetate. The
organic layer was washed with water, brine and dried over sodium
sulfate. The solvent was removed under the reduced pressure to
afford the crude product. The crude product was purified by column
chromatography (60-120 silica gel, 50% ethyl acetate in n-hexane)
to yield the desired product (0.12 g, 66%). .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 8.23 (d, J=1.8 Hz, 1H), 8.06-7.90 (m, 3H),
7.68 (t, J=7.8 Hz, 1H), 7.64 (d, J=11.1 Hz, 1H), 3.92 (s, 8H), 3.12
(s, 3H): LC-MS (ESI): Calculated mass: 421.0; Observed mass
[M+H].sup.+: 422.1 (RT=1.45 min).
Step 2:
5-(6-Fluoro-7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2--
yl)pyrimidin-2-amine
##STR00079##
[0197] To a 50 mL round bottom flask,
4-(2-chloro-6-fluoro-7-(3-(methylsulfonyl)phenyl)quinazolin-4-yl)morpholi-
ne (0.1 g, 0.0002 mol),
(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (0.085
g, 0.0003 mol), cesium carbonate (0.192 g, 0.0005 mol), toluene (5
mL), ethanol (5 mL) and water (2 mL) were added. The reaction
vessel was degassed with N.sub.2 for 5-10 minutes. To the same
reaction mixture, Pd(PPh.sub.3).sub.2Cl.sub.2 (0.008 g, 0.000012
mol) was added and again degassed with N.sub.2 for 5-10 minutes.
The reaction mixture was stirred at 75.degree. C. for 3 hours. The
reaction mixture was cooled and diluted with chloroform. The
organic layer was washed with water, brine and dried over sodium
sulfate. The solvent was removed under the reduced pressure to
afford the crude product. The crude product was purified by column
chromatography (60-120 silica gel, 50% ethyl acetate in n-hexane)
to yield tert-butyl
(5-(6-fluoro-7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)pyr-
imidin-2-yl)carbamate [0.06 g, 43%]. LC-MS (ESI): Calculated mass:
580.1; Observed mass [M+H].sup.+: 581.3 (RT=1.52 min).
[0198] To a 25 mL flask, tert-butyl
(5-(6-fluoro-7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)pyr-
imidin-2-yl)carbamate (0.06 g, 0.0001 mol) and 1,4-dioxane (4 mL)
were added. The reaction mixture was cooled to 0.degree. C. To the
flask, 4 N HCl in 1,4-dioxane (6 mL) was added. The reaction
mixture was stirred at room temperature for 12 hours. The volatiles
were evaporated under reduced pressure to provide the crude
product. The crude product was purified by preparative HPLC (10 mM
ammonium acetate in water and acetonitrile) to provide the title
compound (0.01 g, 7%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.21 (s, 2H), 8.23 (s, 1H), 8.13-8.07 (m, 3H), 8.02 (d, J=11.2 Hz,
1H), 7.88 (t, J=8.0 Hz, 1H), 7.42 (br s, 2H), 3.96 (br s, 4H), 3.84
(br s, 4H), 3.43 (s, 3H): LC-MS (ESI): Calculated mass: 480.1;
Observed mass [M+H].sup.+: 481.1 (RT=0.30 min).
Example 3
N-(3-(2-(2-Aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-p-
henyl)acetamide (Scheme II)
##STR00080##
[0199] Step 1:
N-(3-(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)acetamide
##STR00081##
[0201] To a 100 mL round bottom flask,
4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.5 g,
0.0045 mol--Preparation 3), 3-acetamidophenylboronic acid (0.769 g,
0.0043 mol), sodium carbonate (1.2 g, 0.0113 mol), toluene (30 mL),
ethanol (30 mL) and water (10 mL) were added. The reaction mixture
was degassed with N.sub.2 for 5-10 minutes. To the same reaction
mixture, Pd(PPh.sub.3).sub.2Cl.sub.2 (0.159 g, 0.00022 mol) was
added and again degassed with N.sub.2 for 5-10 minutes. The
reaction mixture was stirred at 95.degree. C. for 2 hours. The
reaction mixture was cooled to room temperature and diluted with
ethyl acetate. The organic layer was washed with water, brine,
dried over anhydrous sodium sulfate and evaporated under reduced
pressure to afford the crude product. The crude product was
purified by column chromatography (60-120 silica gel, 60% ethyl
acetate in hexane) to provide the title compound (1.3 g, 76%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 10.15 (s, 1H), 9.05
(d, J=2.4 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 8.11 (s, 1H), 7.46-7.66
(m, 3H), 4.52 (br s, 4H), 3.81 (t, J=5.1 Hz, 4H), 2.09 (s, 3H):
LC-MS (ESI): Calculated mass: 383.1; Observed mass [M+H].sup.+:
383.8. (RT=1.31 min).
Step 2: tert-Butyl
(5-(7-(3-acetamidophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimid-
in-2-yl)carbamate
##STR00082##
[0203] To a 50 mL sealed tube,
N-(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-phenyl)acetamide
(1.30 g, 0.0033 mol),
(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (1.21 g,
0.0050 mol), potassium phosphate (K.sub.3PO.sub.4) (1.43 g, 0.0067
mol), DMF (35 mL) and water (9 mL) were added. The reaction mixture
was degassed with N.sub.2 for 5-10 minutes. To the same reaction
mixture, Pd(PPh.sub.3).sub.4 (0.274 g, 0.00023 mol) was added and
again degassed with N.sub.2 for 5-10 minutes. The reaction mixture
was stirred at 105.degree. C. for 2 hours. The reaction mass was
cooled and added to ice cold water. The precipitate was obtained
and was collected by filtration. The solid was dissolved in
chloroform, dried over anhydrous sodium sulfate and evaporated
under reduced pressure to provide the crude product. The crude
product was purified by column chromatography (60-120 silica gel,
3% methanol in chloroform) to provide the title compound (1.6 g,
87.4%). NMR (300 MHz, DMSO-d.sub.6): .delta. 10.42 (s, 1H), 10.15
(s, 1H), 9.47 (s, 1H), 9.05 (d, J=2.4 Hz, 1H), 8.29 (d, J=2.1 Hz,
1H), 8.17 (s, 1H), 7.63 (t, J=8.4 Hz, 2H), 7.49 (t, J=7.8 Hz, 1H),
4.56 (br s, 4H), 3.85 (t, J=3.9 Hz, 4H), 2.10 (s, 3H), 1.49 (s,
9H): LC-MS (ESI): Calculated mass: 542.2; Observed mass
[M+H].sup.+: 542.9. (RT=1.39 min).
Step 3:
N-(3-(2-(2-Aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-
-7-yl)phenyl)acetamide
##STR00083##
[0205] To a 250 mL round bottom flask, tert-butyl
(5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-
-yl)carbamate (1.6 g, 0.0029 mol) and DCM (160 mL) were added and
the flask cooled to 0.degree. C. To the reaction flask,
trifluoroacetic acid (16 mL, 10% volume) was added at 0.degree. C.
and the reaction mixture was stirred at room temperature for 3
hours. The volatiles were evaporated under reduced pressure and
methanol was added to provide a solid. The solid was collected by
filtration. The solid was suspended into water and basified with
saturated sodium bicarbonate solution. The reaction mixture was
extracted with chloroform (3.times.200 mL). The organic layer was
washed with water, brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure to provide the crude product.
The crude product was subjected to flash column chromatography
using 4% methanol in chloroform. The obtained solid was washed with
methanol and diethyl ether, filtered and dried under vacuum to
afford the title compound as off-white solid (0.900 g, 69%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.18 (s, 1H), 9.22
(s, 2H), 9.02 (d, J=2.0 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.19 (s,
1H), 7.67 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.54 (t, J=8.0
Hz, 1H), 7.24 (s, 2H), 4.55 (br s, 4H), 3.87 (t, J=4.4 Hz, 4H),
2.12 (s, 3H). LC-MS (ESI): Calculated mass: 442.2; Observed mass
[M+H].sup.+: 443.1. (RT=0.18 min).
Example 4
4-(2-(2-Aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-cy-
clopropylbenzamide (Scheme III)
##STR00084##
[0206] Step 1:
4-(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)benzoic
acid
##STR00085##
[0208] To a 50 mL round bottom flask,
4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.0 g,
0.0030 mol--Preparation 3), 4-carboxyphenylboronic acid (0.5 g,
0.0030 mol), sodium carbonate (0.64 g, 0.0060 mol) dioxane (60 mL),
ethanol (10 mL) and water (10 mL) were added. The reaction mixture
was degassed with N.sub.2 for 5-10 minutes. To the same reaction
mixture, Pd(PPh.sub.3).sub.2Cl.sub.2 (0.106 g, 0.00015 mol) was
added and degassed with N.sub.2 for 5-10 minutes. The reaction
mixture was stirred at 90.degree. C. for 2 hours. The volatiles
were evaporated to provide a residue. The residue was stirred with
water and acidified with 2 N hydrochloric acid to pH 5-6 to provide
a precipitate. The precipitate was collected by filtration and
dried under reduced pressure to afford the title compound (0.8 g,
71%). The compound was used in the next step without further
purification. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 9.18 (d,
J=2.4 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.10-8.03 (m, 4H), 4.58 (br
s, 4H), 3.79 (t, J=4.5 Hz, 4H): LC-MS (ESI): Calculated mass:
370.0; Observed mass [M+H].sup.+: 371.1 (RT=1.37 min).
Step 2:
4-(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-cyclopropyl-
benzamide
##STR00086##
[0210] To a 50 mL round bottom flask,
4-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)benzoic acid
(0.2 g, 0.00054 mol), cyclopropyl amine (0.046 g, 0.00081 mol) and
DMF (10 mL) were added. To the same flask, HATU (0.3 g, 0.00081
mol) and TEA (0.23 mL, 0.0018 mol) were added. The reaction mixture
was stirred at room temperature for 12 hours. The reaction mixture
was diluted with 10% methanol in chloroform and washed with water.
The organic layer was washed with brine, dried over anhydrous
sodium sulfate and evaporated under reduced pressure to provide the
crude product. The crude product was purified by flash column
chromatography (0-1% methanol in chloroform) to provide the title
compound (0.15 g, 68%). .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 9.21 (d, J=2.4 Hz, 1H), 8.59 (d, J=4.2 Hz, 1H), 8.42 (d,
J=2.4 Hz, 1H), 7.94-8.06 (m, 4H), 4.52 (br s, 4H), 3.80 (t, J=4.8
Hz, 4H), 2.88-2.90 (m, 1H), 0.60-0.62 (m, 2H), 0.70-0.73 (m, 2H):
LC-MS (ESI): Calculated mass: 409.1; Observed mass [M+H].sup.+:
410.1. (RT=1.34 min).
Step 3: tert-Butyl
(5-(7-(4-(cyclopropylcarbamoyl)phenyl)-4-morpholinopyrido[3,2-d]-pyrimidi-
n-2-yl)pyrimidin-2-yl)carbamate
##STR00087##
[0212] To a 50 mL sealed tube,
4-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-N-cyclo-propylbenzam-
ide (0.15 g, 0.00036 mol),
(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (0.113
g, 0.00047), potassium phosphate (0.155 g, 0.00072 mol), DMF (10
mL) and water (2 mL) were added. The reaction mixture was degassed
with N.sub.2 for 5-10 minutes. To the same reaction mixture,
Pd(PPh.sub.3).sub.4 (0.022 g, 0.000018 mol) was added and degassed
with N.sub.2 for 5-10 minutes. The reaction mixture was stirred at
95.degree. C. for 1 hour. The reaction mass was cooled to room
temperature and added ice cold water. A precipitate was obtained
and the solid was collected by filtration. The solid was dissolved
in chloroform, dried over anhydrous sodium sulfate and evaporated
under reduced pressure to provide the crude product. The crude
product was purified by flash column chromatography (2% methanol in
chloroform) to provide the title compound (0.1 g, 48%). .sup.1H NMR
(300 MHz, DMSO-d.sub.6): .delta. 10.41 (br s, 1H), 9.47 (s, 1H),
9.19 (d, J=1.8 Hz, 1H), 6.59 (d, J=4.2 Hz, 1H), 8.51 (d, J=1.8 Hz,
1H), 7.98-8.08 (m, 4H), 4.57 (br s, 4H), 3.83 (s, 4H), 2.88-2.89
(m, 1H), 1.48 (s, 9H), 0.73 (d, J=5.4 Hz, 2H), 0.61 (d, J=3.0 Hz,
2H): LC-MS (ESI): Calculated mass: 568.2; Observed mass
[M+H].sup.+: 569.2. (RT=1.57 min).
Step 4:
4-(2-(2-Aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7--
yl)-N-cyclo-propyl benzamide
##STR00088##
[0214] To a 50 mL round bottom flask, tert-butyl
(5-(7-(4-(cyclopropylcarbamoyl)phenyl)-4-morpholinopyrido[3,2-d]pyrimidin-
-2-yl)pyrimidin-2-yl)carbamate (0.1 g, 0.00018 mol) and DCM (10 mL)
were added. To the same reaction flask, TFA (0.055 mL, 0.00072 mol)
was added and the reaction mixture was stirred at room temperature
for 12 hours. The volatiles were evaporated under reduced pressure
to provide crude residue. The residue was dissolved in 10% methanol
in chloroform, washed with saturated sodium bicarbonate solution,
brine, dried over sodium sulfate and evaporated under reduced
pressure to provide the crude product. The crude product was
purified by flash column chromatography (3-4% methanol in
chloroform) to provide the title compound (0.016 g, 12%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 9.19 (br s, 2H), 9.12 (d,
J=1.6 Hz, 1H), 8.58 (d, J=4.0 Hz, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.07
(d, J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 2H), 7.22 (br s, 2H), 4.52
(br s, 4H), 3.83 (s, 4H), 2.93-2.86 (m, 1H), 0.72 (d, J=5.2 Hz,
2H), 0.61 (d, J=2.4 Hz, 2H): LC-MS (ESI): Calculated mass: 468.2;
Observed mass [M+H].sup.+: 469.0. (RT=0.19 min).
Example 5
(5-(2-(2-Aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)fura-
n-2-yl)(4-methylpiperazin-1-yl)methanone (Scheme III)
##STR00089##
[0215] Step 1:
5-(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carbaldehyde
##STR00090##
[0217] To a 50 mL round bottom flask,
4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (0.5 g,
0.0015 mol--Preparation 3), 5-formyl-2-furanylboronic acid (0.21 g,
0.0015 mol), sodium carbonate (0.32 g, 0.003 mol), toluene (20 mL),
ethanol (10 mL) and water (5 mL) were added. The reaction vessel
was degassed with N.sub.2 for 5-10 minutes. To the same reaction
mixture, Pd(PPh.sub.3).sub.2Cl.sub.2 (0.053 g, 0.000075 mol) was
added and again degassed with N.sub.2 for 5-10 minutes. The
reaction mixture was stirred at 95.degree. C. for 2 hours. The
reaction mixture was cooled and diluted with ethyl acetate. The
organic layer was washed with water, brine and dried over sodium
sulfate. The solvent was removed under reduced pressure to afford
the crude product. The crude product was purified by column
chromatography (60-120 silica gel, 60% ethyl acetate in n-hexane)
to yield the desired product (0.38 g, 72%). .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 9.77 (s, 1H), 9.12 (d, J=2.1 Hz, 1H), 8.34 (d,
J=2.1 Hz, 1H), 7.40 (d, J=3.6 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 4.50
(br s, 4H), 3.91-3.88 (m, 4H): LC-MS (ESI): Calculated mass: 344.0;
Observed mass [M+H].sup.+: 345.0 (RT=1.39 min).
Step 2: Methyl
5-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carboxylate
##STR00091##
[0219] To a 100 mL flask,
5-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carbaldehyde
(0.38 g, 0.0011 mol) and methanol (30 mL) were added and the
solution cooled to 0.degree. C. To the reaction mixture, manganese
(IV) oxide (0.191 g, 0.0022 mol) and sodium cyanide (0.109 g,
0.0022 mol) were added at 0.degree. C. The reaction mixture was
stirred at 0.degree. C. for 3 hours. The reaction mixture was
diluted with ethyl acetate. The organic layer was washed with
water, brine, dried over anhydrous sodium sulfate and was
evaporated under reduced pressure to provide methyl
5-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carboxylate
as a solid (0.35 g). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
9.19 (d, J=2.1 Hz, 1H), 8.29 (d, J=2.1 Hz, 1H), 7.62 (d, J=3.6 Hz,
1H), 7.54 (d, J=3.6 Hz, 1H), 4.84-4.10 (br s, 4H), 3.87 (s, 3H),
3.81 (t, J=4.8 Hz, 4H): LC-MS (ESI): Calculated mass: 374.0;
Observed mass [M+H].sup.+: 375.0 (RT=1.51 min).
Step 3:
5-(2-(2-(tert-Butoxycarbonyl)amino)pyrimidin-5-yl)-4-morpholinopyr-
ido[3,2-d]pyrimidin-7-yl)furan-2-carboxylic acid
##STR00092##
[0221] To a 50 mL sealed tube, methyl
5-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)furan-2-carboxylate
(0.35 g, 0.0009 mol),
(2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (0.33 g,
0.0014 mol), potassium phosphate (0.39 g, 0.0018 mol), DMF (15 mL)
and water (5 mL) were added. The reaction mixture was degassed with
N.sub.2 for 5-10 minutes. To the same reaction mixture,
Pd(PPh.sub.3).sub.4 (0.053 g, 0.000046 mol) was added and the
mixture was degassed again with N.sub.2 for 5-10 minutes. The
reaction mixture was stirred at 95.degree. C. for 1 hour. The
reaction mixture was cooled and mixed with water. A precipitate
formed which was collected by filtration. The filtered solid was
purified by flash column chromatography (3% methanol in chloroform)
to provide methyl
5-(2-(2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)-4-morpholinopy-
rido[3,2-d]pyrimidin-7-yl)furan-2-carboxylate (0.3 g). LC-MS (ESI):
Calculated mass: 533.0; Observed mass: 434.1 [M-Boc+H].sup.+
(RT=1.60 min).
[0222] Methyl
5-(2-(2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)-4-morpholinopyrido[3,2-
-d]-pyrimidin-7-yl)furan-2 carboxylate (0.3 g, 0.0006 mol) was
taken into a 25 mL round bottom flask and lithium hydroxide
monohydrate (0.23 g, 0.006 mol), THF (5 mL), methanol (5 mL), and
water (5 mL) were added. The reaction mixture was stirred at room
temperature for 3 hours. The volatiles were evaporated under
reduced pressure to afford a residue. The residue was neutralized
with 2N hydrochloric acid and extracted with DCM. The organic layer
was washed with water and brine, dried over anhydrous sodium
sulfate and evaporated to provide the title compound (0.2 g, 68%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 10.40 (s, 1H), 9.43
(s, 1H), 9.17 (d, J=2.1 Hz, 1H), 8.39 (d, J=2.1 Hz, 1H), 7.58 (d,
J=3.6 Hz, 1H), 7.41 (d, J=3.6 Hz, 1H), 4.51 (br s, 4H), 3.82 (br s,
4H), 1.48 (s, 9H): LC-MS (ESI): Calculated mass: 519.1; Observed
mass [M+H].sup.+: 520.0 (RT=0.99 min).
Step 4: tert-Butyl
(5-(7-(5-(4-methylpiperazine-1-carbonyl)furan-2-yl)-4-morpholino-pyrido[3-
,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate
##STR00093##
[0224] To a 25 mL flask,
5-(2-(2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)-4-morpholinopyrido[3,2-
-d]pyrimidin-7-yl)furan-2-carboxylic acid (0.1 g, 0.0002 mol),
N-methylpiperazine (0.02 g, 0.0003 mol), HATU (0.14 g, 0.0004 mol),
triethyl amine (0.055 mL, 0.0004 mol) and DMF (10 mL) were added.
The reaction mixture was stirred at room temperature for 12 hours.
To the reaction mixture, chloroform and water were added. The
organic layer was washed with brine, dried over sodium sulfate and
evaporated under reduced pressure to provide the crude product. The
crude product was purified by flash column chromatography (3%
methanol in chloroform) to yield the title compound (0.06 g, 52%).
LC-MS (ESI): Calculated mass: 601.2; Observed mass [M-Boc+H].sup.+:
502.2 (RT=0.11 min).
Step 5:
(5-(2-(2-Aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-
-yl)furan-2-yl)(4-methylpiperazin-1-yl)-methanone
##STR00094##
[0226] To a 25 mL flask, tert-butyl
(5-(7-(5-(4-methylpiperazine-1-carbonyl)furan-2-yl)-4-morpholinopyrido[3,-
2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (0.06 g, 0.0001 mol)
and DCM (10 mL) were added. To the reaction mixture,
trifluoroacetic acid (0.076 mL, 0.001 mol) was added. The reaction
mixture was stirred at room temperature for 3 hours. The volatiles
were evaporated under reduced pressure to provide a residue. The
residue was basified to pH 8.0 with saturated sodium bicarbonate
solution and extracted with DCM. The organic layer was washed with
water and brine, dried over sodium sulfate and evaporated to
provide the crude product. The crude product was purified by
preparative TLC (5% methanol in chloroform) to provide the title
compound (0.01 g, 20%). .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 9.39 (s, 2H), 9.02 (d, J=2.4; H, 1H), 8.35 (d, J=2.0 Hz,
1H), 7.23 (d, J=3.6 Hz, 1H), 7.08 (d, J=3.6 Hz, 1H), 5.40 (br s,
2H), 4.63 (br s, 4H), 3.99 (t, J=4.8 Hz, 8H), 2.61 (t, J=4.4 Hz,
4H), 2.43 (s, 3H): LC-MS (ESI): Calculated mass: 501.2; Observed
mass [M+H].sup.+: 502.0 (RT=0.08 min).
Example 6
N-(3-(2-(2-Aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)phenyl)-2-hydr-
oxy-2-methylpropanamide (Scheme IVa)
##STR00095##
[0227] Step 1: 3-(2-Chloro-4-morpholinoquinazolin-7-yl)aniline
##STR00096##
[0229] To a 50 mL round bottom flask,
4-(7-bromo-2-chloroquinazolin-4-yl)morpholine (1.0 g, 0.0030
mol--Preparation 1), 3-aminophenylboronic acid pinacol ester (0.657
g, 0.0030 mol), sodium carbonate (0.635 g, 0.0060 mol), toluene (20
mL), ethanol (4 mL) and water (3 mL) were added. The reaction
mixture was degassed with N.sub.2 for 5-10 minutes. To the same
reaction mixture, Pd(PPh.sub.3).sub.2Cl.sub.2 (0.105 g, 0.00015
mol) was added and degassed with N.sub.2 for 5-10 minutes. The
reaction mixture was stirred at 95.degree. C. for 2 hours. The
reaction mixture was cooled and diluted with ethyl acetate. The
organic layer was washed with water, brine, dried over anhydrous
sodium sulfate and evaporated under reduced pressure to afford the
crude product. The crude product was purified by flash column
chromatography (40% ethyl acetate in hexane) to provide the title
compound (0.65 g, 62%). .sup.1H NMR (400 MHz, CDCl.sub.3,): .delta.
8.00 (d, J=1.6 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.66 (dd, J'=8.4
Hz, J''=1.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.08 (d, J=8.0 Hz,
1H), 6.99 (t, J=2.0 Hz, 1H), 6.77 (dd, J'=7.6 Hz, J''=1.2 Hz, 1H),
3.90 (s, 8H), 3.84 (br s, 2H), LC-MS (ESI): Calculated mass.
340.11, Observed mass [M+H].sup.+: 341.1 (RT=0.48 min).
Step 2: tert-Butyl
(5-(7-(3-aminophenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-yl)-carbama-
te
##STR00097##
[0231] In 50 mL round bottom flask,
3-(2-chloro-4-morpholinoquinazolin-7-yl)aniline (0.6 g, 0.0018
mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid
(0.506 g, 0.0022), potassium phosphate (1.08 g, 0.0054 mol),
1,4-dioxane (20 mL) and water (5 mL) were added. The reaction
mixture was degassed with N.sub.2 for 5-10 minutes. To the same
reaction mixture, Pd (PPh.sub.3).sub.4 (0.098 g, 0.00009 mol) was
added and degassed with N.sub.2 for 5-10 minutes. The reaction
mixture was stirred at 95.degree. C. for 2 hours. The reaction mass
was cooled to room temperature and water was added. The crude
product was extracted with ethyl acetate (3.times.100 mL). The
combined organic layer was washed with brine, dried over sodium
sulfate and evaporated under reduced pressure to provide the crude
product. The crude product was purified by flash column
chromatography (2% methanol in chloroform) to provide the title
compound (0.3 g, 34%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
10.40 (s, 1H), 9.49 (s, 2H), 8.12 (d, J=8.8 Hz, 1H), 8.01 (d, J=1.6
Hz, 1H), 7.75 (dd, J'=8.8 Hz, J''=1.6 Hz, 1H), 7.20 (t, J=7.6 Hz,
1H), 7.04 (br s, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.66 (d, J=8.4 Hz,
1H), 5.29 (s, 2H), 3.90 (d, J=4.4 Hz, 4H), 3.84 (d, J=4.0 Hz, 4H),
1.49 (s, 9H): LC-MS (ESI): Calculated mass. 499.2, Observed mass
[M+H].sup.+: 500.4. (RT=0.78 min).
Step 3: tert-Butyl
(5-(7-(3-(2-hydroxy-2-methylpropanamido)phenyl)-4-morpholinoquinazolin-2--
yl)pyrimidin-2-yl)carbamate
##STR00098##
[0233] In a 25 mL round bottom flask, tert-butyl
(5-(7-(3-aminophenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-yl)carbamat-
e (0.1 g, 0.0002 mol), 2-hydroxy-2-methylpropanoic acid (0.052 g,
0.0005 mol) and DMF (10 mL) were added. To the flask, HATU (0.152
g, 0.0004 mol) and TEA (0.081 mL, 0.0006 mol) were added and then
stirred at room temperature for 12 hours. To the reaction mixture
was added water to provide a precipitate. The precipitate was
collected by filtration to provide the crude product. The crude
product was purified by flash column chromatography (2% methanol in
chloroform) to obtain the title compound (0.06 g, 60%). LC-MS (ESI)
Calculated mass. 585.2, Observed mass [M+H].sup.+: 586.1 (RT=0.83
min).
Step 4:
N-(3-(2-(2-Aminopyrimidin-5-yl)-4-morpholinoquinazolin-7-yl)phenyl-
)-2-hydroxy-2-methylpropanamide
##STR00099##
[0235] In a 25 mL round bottom flask, tert-butyl
(5-(7-(3-(2-hydroxy-2-methylpropanamido)phenyl)-4-morpholinoquinazolin-2--
yl)pyrimidin-2-yl)carbamate (0.06 g, 0.0001 mol) and DCM (10 mL)
were added. To the flask was added trifluoroacetic acid (0.5 mL)
and the reaction stirred at room temperature for 5 hours. The
volatiles were evaporated under reduced pressure to provide the
residue. The residue was dissolved in 5% methanol in DCM and washed
with saturated sodium bicarbonate. The organic layer was washed
with water, brine, dried over sodium sulfate and evaporated under
reduced pressure to provide the crude product. The crude product
was purified by preparative HPLC (10 mM NH.sub.4OAc and 1:1
MeOH:ACN) to obtain the title compound (0.007 mg, 14%). .sup.1H NMR
(DMSO-d.sub.6, 400 MHz): .delta. 9.76 (s, 1H), 9.22 (s, 2H), 8.32
(s, 1H), 8.11 (d, J=8.8 Hz, 1H), 8.05 (s, 1H), 7.87 (d, J=8.0 Hz,
1H), 7.77 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.48 (t, J=8.8
Hz, 1H), 7.16 (s, 2H), 3.85 (s, 8H), 1.39 (s, 6H): LC-MS (ESI):
Calculated mass. 485.2, Observed mass [M+H].sup.+: 486.2. (RT=0.11
min).
Example 7
N-(3-(2-(2-Aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-p-
henyl)cyclopropanecarboxamide (Scheme IVa)
##STR00100##
[0236] Step 1:
3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)aniline
##STR00101##
[0238] To a 100 mL round bottom flask,
4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.5 g,
0.0046 mol--Preparation 2), 3-aminophenylboronic acid (0.67 g,
0.0051 mol), sodium carbonate (0.98 g, 0.0092 mol) toluene (30 mL),
ethanol (10 mL) and water (5 mL) were added. The reaction mixture
was degassed with N.sub.2 for 5-10 minutes. To the same reaction
mixture, Pd(PPh.sub.3).sub.2Cl.sub.2 (0.14 g, 0.0002 mol) was added
and again degassed with N.sub.2 for 5-10 minutes. The reaction
mixture was stirred at 90.degree. C. for 2 hours. The reaction
mixture was cooled and diluted with ethyl acetate. The organic
layer was washed with water, brine, dried over anhydrous sodium
sulfate and evaporated under reduced pressure to afford the crude
product. The crude product was purified by column chromatography
(60-120 silica gel, 60% ethyl acetate in hexane) to provide the
title compound (1.1 g, 70%). .sup.1H NMR (300 MHz, DMSO-d.sub.6):
.delta. 9.02 (d, J=2.1 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.22 (t,
J=7.8 Hz, 1H), 7.01-6.99 (m, 2H), 6.68-6.17 (m, 1H), 5.33 (br s,
2H), 4.52 (br s, 4H), 3.79 (t, J=4.8 Hz, 4H). LC-MS (ESI):
Calculated mass: 341.1; Observed mass [M+H].sup.+: 342.1. (RT=0.73
min).
Step 2: tert-butyl
(5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-
-yl)carbamate
##STR00102##
[0240] To a 50 mL sealed tube,
3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)aniline (1.1 g,
0.0032 mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic
acid (1.15 g, 0.0048), potassium phosphate (2.04 g, 0.0096 mol),
DMF (20 mL) and water (7 mL) were added. The reaction mixture was
degassed with N.sub.2 for 5-10 minutes. To the same reaction
mixture, Pd(PPh.sub.3).sub.4 (0.23 g, 0.0002 mol) was added and
degassed with N.sub.2 for 5-10 minutes. The reaction mixture was
stirred at 105.degree. C. for 1 hour. The reaction mass was cooled
to room temperature and added ice cold water. The precipitate was
obtained and the solid was collected by filtration. The solid was
dissolved in chloroform, dried over anhydrous sodium sulfate and
evaporated under reduced pressure to provide the crude product. The
crude product was purified by column chromatography (60-120 silica
gel, 2% methanol in chloroform) to provide the title compound (1.4
g, 87%). .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 10.42 (s,
1H), 9.47 (s, 1H), 9.02 (d, J=2.4 Hz, 1H), 8.24 (d, J=2.1 Hz, 1H),
7.23 (t, J=7.8 Hz, 1H), 7.07-7.03 (m, 2H), 6.71 (d, J=8.1 Hz, 1H),
5.33 (s, 2H), 4.55 (br s, 4H), 3.83 (t, J=4.8 Hz, 4H), 1.49 (s,
9H). LC-MS (ESI): Calculated mass: 500.2; Observed mass
[M+H].sup.+: 501.1 (RT=1.09 min).
Step 3: tert-butyl
(5-(7-(3-(cyclopropanecarboxamido)phenyl)-4-morpholinopyrido[3,2-d]pyrimi-
din-2-yl)pyrimidin-2-yl)carbamate
##STR00103##
[0242] To a 25 mL round bottom flask, tert-butyl
(5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-
-yl)carbamate (0.2 g, 0.0004 mol), cyclopropane carboxylic acid
(0.041 g, 0.00048 mol) and DMF (8 mL) were added. To the same
flask, HATU (0.46 g, 0.0012 mol) and TEA (0.22 mL, 0.0016 mol) were
added. The reaction mass was stirred at room temperature for 12
hours. The volatiles were evaporated to dryness under reduced
pressure to provide a residue. The residue was stirred with water
to provide a solid and the solid was collected by filtration. The
solid was washed with diethyl ether to provide the crude product.
The crude product was purified by flash column chromatography (1-2%
methanol in chloroform) to afford the title compound (0.15 g, 66%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 10.42 (br s, 2H), 9.48
(s, 1H), 9.07 (d, J=2.4 Hz, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.20 (s,
1H), 7.47-7.67 (m, 3H), 4.57 (br s, 4H), 3.84 (s, 4H), 1.84-1.80
(m, 1H), 1.49 (s, 9H), 0.85-0.83 (m, 4H): LC-MS (ESI): Calculated
mass: 568.2; Observed mass [M+H].sup.+: 569.2 (RT=1.56 min).
Step 4:
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-
-7-yl)phenyl)cyclopropanecarboxamide
##STR00104##
[0244] To a 50 mL round bottom flask, tert-butyl
(5-(7-(3-(cyclopropanecarboxamido)phenyl)-4-morpholinopyrido[3,2-d]pyrimi-
din-2-yl)pyrimidin-2-yl)carbamate (0.15 g, 0.00026 mol) and DCM (10
mL) were added and then cooled to 0.degree. C. To the same reaction
flask, trifluoroacetic acid (0.12 g, 0.00104 mol) was added at
0.degree. C. and the reaction mixture was stirred at room
temperature for 12 hours. The reaction mixture was quenched with
saturated sodium bicarbonate solution and extracted with 10%
methanol in chloroform. The organic layer was washed with water,
brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure to provide the crude product. The crude product
was subjected to flash column chromatography using 3-4% methanol in
chloroform. The obtained solid was washed diethyl ether, filtered
and dried under vacuum to afford the title compound (0.1 g, 81%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.44 (s, 1H), 9.23
(s, 2H), 9.04 (d, J=2.4 Hz, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.23 (s,
1H), 7.68-7.50 (m, 3H), 7.24 (br s, 2H), 4.55 (br s, 4H), 3.86 (d,
J=4.0 Hz, 4H), 1.85-1.83 (m, 1H), 0.87-0.85 (m, 4H): LC-MS (ESI):
Calculated mass: 468.2; Observed mass [M+H].sup.+: 469.1. (RT=0.35
min).
Example 8
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)ph-
enyl)-4-fluorobenzenesulfonamide (Scheme IVb)
##STR00105##
[0245] Step 1: tert-butyl
(5-(7-(3-(4-fluorophenylsulfonamido)phenyl)-4-morpholinopyrido[3,2-d]-pyr-
imidin-2-yl)pyrimidin-2-yl)carbamate
##STR00106##
[0247] To a 25 mL flask, tert-butyl
(5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-
-yl)carbamate (Example 7, Step 2) (0.1 g, 0.0002 mol) and pyridine
(4 mL) were added. To the same flask, 4-fluorobenzenesulfonyl
chloride (0.038 g, 0.0002 mol) was added. The reaction mixture was
stirred at room temperature for 12 hours. The reaction mixture was
diluted with 10% methanol in chloroform and washed with water. The
organic layer was washed with brine, dried over sodium sulfate and
was evaporated to provide the crude product. The crude product was
purified by flash column chromatography (3% methanol in chloroform)
to obtain the title compound (0.06 g, 45%). .sup.1H NMR (300 MHz,
DMSO-d.sub.6): .delta. 10.57 (s, 1H), 10.42 (s, 1H), 9.48 (s, 1H),
8.98 (d, J=2.1 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 7.91 (dd, J'=5.1
Hz, J''=3.9 Hz, 2H), 7.65 (d, J=7.8 Hz, 1H), 7.56 (s, 1H), 7.45
(dd, J'=8.7 Hz, J''=1.5 Hz, 3H), 7.23 (d, J=7.8 Hz, 1H), 4.57 (br
s, 4H), 3.83 (br s, 4H), 1.49 (s, 9H). LC-MS (ESI): Calculated
mass: 658.2; Observed mass [M+H].sup.+: 658.9 (RT=1.69 min).
Step 2:
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-
-7-yl)phenyl)-4-fluorobenzenesulfonamide
##STR00107##
[0249] To a 25 mL flask, tert-butyl
(5-(7-(3-(4-fluorophenylsulfonamido)phenyl)-4-morpholino-pyrido[3,2-d]pyr-
imidin-2-yl)pyrimidin-2-yl)carbamate (0.06 g, 0.00009 mol) and DCM
(9 mL) were added. To the same reaction vessel, trifluoroacetic
acid (0.5 mL) was added. The reaction mixture was stirred at room
temperature for 3 hours. The volatiles were evaporated under
reduced pressure to provide the residue. The residue was washed
with ether and was dissolved in 10% methanol in DCM. The organic
layer was basified with saturated sodium bicarbonate solution (pH
8.0). The organic layer was washed with water, brine, dried over
sodium sulfate and evaporated under reduced pressure to provide the
crude product. The crude product was washed with methanol and
diethyl ether to provide the solid. The solid was dried under high
vacuum to provide the title compound (0.031 g, 60%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 10.57 (s, 1H), 9.20 (s, 2H), 8.92
(d, J=2.4 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H), 7.90-7.87 (m, 2H), 7.63
(d, J=7.6 Hz, 1H), 7.55 (br s, 1H), 7.46-7.40 (m, 3H), 7.22 (br s,
2H), 7.20 (s, 1H) 4.52 (br s, 4H), 3.84 (t, J=4.4 Hz, 4H). LC-MS
(ESI): Calculated mass: 558.1; Observed mass [M+H].sup.+: 558.9
(RT=1.19 min).
Example 9
N-(3-(2-(2-Aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-p-
henyl)-2-(4-hydroxypiperidin-1-yl)acetamide (Scheme IVc)
##STR00108##
[0250] Step 1: tert-Butyl
(5-(7-(3-(2-chloroacetamido)phenyl)-4-morpholinopyrido[3,2-d]-pyrimidin-2-
-yl)pyrimidin-2-yl)carbamate
##STR00109##
[0252] To a 25 mL round bottom flask, tert-butyl
(5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-
-yl)carbamate (Example 7, Step 2) (0.15 g, 0.0003 mol),
chloroacetyl chloride (0.051 g, 0.00045 mol) and DCM (10 mL) were
added and then cooled to 10oC. To the same reaction flask,
triethylamine (0.12 mL, 0.0009 mol) was added. The reaction mass
was stirred at room temperature for 30 minutes. The reaction
mixture was diluted with DCM, washed with water and brine. The
organic layer was dried over anhydrous sodium sulfate and
evaporated to provide the crude product. The crude product was
purified by column chromatography (60-120 silica-gel and 0-2%
methanol in chloroform) to afford the title compound (0.15 g, 87%).
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 10.52 (s, 1H), 10.42
(s, 1H), 9.48 (s, 1H), 9.08 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.1 Hz,
1H), 8.18 (s, 1H), 7.68 (t, J=4.8 Hz, 2H), 7.57 (t, J=7.8 Hz, 1H),
4.65-4.52 (br s, 4H), 4.33 (s, 2H), 3.84 (s, 4H), 1.49 (s, 9H):
LC-MS (ESI): Calculated mass. 576.2, Observed mass [M+H].sup.+:
577.2 (RT=1.53 min).
Step 2: tert-butyl
(5-(7-(3-(2-(4-hydroxypiperidin-1-yl)acetamido)phenyl)-4-morpholino-pyrid-
o[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate
##STR00110##
[0254] To a 25 mL round bottom flask, 4-hydroxy piperidine (0.021
g, 0.00021 mol) and DMF (1.5 mL) were added and then cooled to
0-10oC. To the same reaction flask, potassium carbonate (0.058 g,
0.00042 mol) was added and the reaction mixture was stirred at
0-10.degree. C. for 30 minutes. To the same flask, a solution of
tert-butyl
(5-(7-(3-(2-chloroacetamido)phenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2--
yl)pyrimidin-2-yl)carbamate (0.08 g, 0.00014 mol) in DMF (1 mL) was
added and then stirred at room temperature for 12 hours. The
reaction was quenched with water to provide the precipitate. The
precipitate was collected by filtration to provide the title
compound (0.078 g, 88%). The compound was used in the next step
without purification. .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta.
10.43 (s, 1H), 9.84 (s, 1H), 9.49 (s, 1H), 9.12 (d, J=2.1 Hz, 1H),
8.38 (s, J=2.1 Hz, 1H), 8.21 (br s, 1H), 7.87 (d, J=7.8 Hz, 1H),
7.68 (d, J=7.8 Hz, 1H), 7.54 (t, J=8.1 Hz, 1H), 4.63 (d, J=3.9 Hz,
1H), 4.58 (br s, 4H), 3.84 (s, 4H), 3.51-3.49 (m, 1H), 3.28 (s,
2H), 3.13-2.75 (m, 2H), 2.29 (t, J=8.7 Hz, 2H), 1.78 (d, J=9.3 Hz,
2H), 1.58 (d, J=9.3 Hz, 2H), 1.49 (s, 9H): LCMS (ESI): Calculated.
641.3, Observed mass [M+H].sup.+: 642.2, (RT=0.22 min).
Step 3:
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-
-7-yl)phenyl)-2-(4-hydroxypiperidin-1-yl)acetamide
##STR00111##
[0256] To a 25 mL round bottom flask, tert-butyl
(5-(7-(3-(2-(4-hydroxypiperidin-1-yl)acetamido)phenyl)-4-morpholinopyrido-
[3,2-d]pyrimidin-2-1)pyrimidin-2-yl)carbamate (0.078 g, 0.00012 mol
and DCM (15 mL) was added. To the same flask, TFA (0.037 mL,
0.00048 mol) was added and the reaction mixture stirred at room
temperature for 12 hours. The volatiles were evaporated under
reduced pressure to provide the residue. The residue was dissolved
in 10% methanol in chloroform. The organic layer was washed with
water, brine, dried over sodium sulfate and evaporated under
reduced pressure to provide the crude product. The crude product
was purified by preparative TLC (5% methanol in chloroform, 3 times
eluted) to provide the title compound (0.065 g, 99%). .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 9.86 (s, 1H), 9.23 (s, 2H), 9.08
(d, J=1.6 Hz, 1H), 8.34 (d, J=1.6 Hz, 1H), 8.22 (s, 1H), 7.89 (d,
J=8.4 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.24
(s, 2H), 4.66 (d, J=3.6 Hz, 1H), 4.56 (br s, 4H), 3.86 (s, 4H),
3.53-3.48 (m, 1H), 3.15 (s, 2H), 2.81-2.78 (m, 2H), 2.31 (t, J=9.6
Hz, 2H), 1.80-1.78 (m, 2H), 1.60-1.55 (m, 2H): LC-MS (ESI):
Calculated mass. 541.25, Observed mass [M+H].sup.+: 542.3 (RT=0.10
min).
Example 10
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)-p-
henyl)morpholine-4-carboxamide (Scheme IVd)
##STR00112##
[0257] Step 1: tert-butyl
(5-(7-(3-(morpholine-4-carboxamido)phenyl)-4-morpholinopyrido[3,2-d]pyrim-
idin-2-yl)pyrimidin-2-yl)carbamate
##STR00113##
[0259] To a 25 mL round bottom flask, tert-butyl
(5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-
-yl)carbamate (Example 7, Step 2) (0.1 g, 0.0002 mol),
2,2,2,-trichloroethyl chloroformate (0.05 g, 0.00024 mol) and THF
(5 mL) were added. The reaction mixture was cooled to 0.degree. C.
To the same flask, triethylamine (0.055 mL, 0.0004 mol) was added.
The reaction mixture was stirred at room temperature for 30
minutes. The volatiles were removed under reduced pressure to
provide crude residue. The crude residue was dissolved in
chloroform. The organic layer was washed with water, brine, dried
over anhydrous sodium sulfate and evaporated under reduced pressure
to afford the intermediate (0.13 g, 96%) and was taken for the next
step without further purification.
[0260] To a 10 mL round bottom flask, the compound immediately
above (0.07 g, 0.0001 mol), morpholine (0.018 g, 0.0002 mol),
triethylamine (0.07 mL, 0.0005 mol) and toluene (2 mL) were added.
The reaction mixture was stirred at 110oC for 4 hours. The
volatiles were evaporated to provide a residue. The residue was
dissolved in chloroform. The organic layer was washed with water,
brine, dried over anhydrous sodium sulfate and evaporated under
reduced pressure to afford the crude product. The crude product was
purified by column chromatography (60-120 silica gel, 0-5% methanol
in chloroform) followed by preparative TLC (4% methanol in
chloroform) to provide the title compound (0.04 g, 63%). .sup.1H,
NMR (300 MHz, DMSO-d.sub.6): .delta. 10.42 (s, 1H), 9.47 (s, 1H),
9.08 (d, J=2.1 Hz, 1H), 8.73 (s, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.05
(s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.46 (t,
J=7.8 Hz, 1H), 4.57 (br s, 4H), 3.83 (s, 4H), 3.65-3.62 (m, 4H),
3.48-3.46 (m, 4H), 1.48 (s, 9H). LC-MS (ESI): Calculated mass.
613.2, Observed mass [M+H].sup.+: 613.8, (RT=1.37 min).
Step 2:
N-(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-
-7-yl)phenyl)-morpholine-4-carboxamide
##STR00114##
[0262] To a 25 mL round bottom flask, tert-butyl
(5-(7-(3-(morpholine-4-carboxamido)phenyl)-4-morpholinopyrido[3,2-d]pyrim-
idin-2-yl)pyrimidin-2-yl)carbamate (0.035 g, 0.00006 mol) and DCM
(5 mL) were added. To the same flask, TFA (0.013 g, 0.00012 mol)
was added and the mixture stirred at room temperature for 3 hours.
The volatiles were evaporated under reduced pressure to provide the
crude residue. The crude residue was dissolved in 10% methanol in
chloroform and washed with aqueous saturated sodium bicarbonate.
The organic layer was washed with water, brine, dried over
anhydrous sodium sulfate and evaporated under reduced pressure to
provide the crude product. The crude product was purified by
preparative TLC (4% methanol in chloroform, double elution) to
provide the title compound (0.015 g, 52%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.19 (s, 2H), 9.02 (d, J=2.4 Hz, 1H), 8.72
(s, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.04 (t, J=1.6 Hz, 1H), 7.64 (d,
J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.20
(br s, 2H), 4.52 (br s, 4H), 3.84 (t, J=4.8 Hz, 4H), 3.65 (t, J=4.4
Hz, 4H), 3.48 (t, J=4.8 Hz, 4H): LC-MS (ESI): Calculated mass.
513.2, Observed mass [M+H].sup.+: 514.2 (RT=0.19 min).
Example 11
1-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)--
methyl)piperazin-1-yl)-2-hydroxypropan-1-one (Scheme V)
##STR00115##
[0263] Step 1:
2-chloro-4-morpholinopyrido[3,2-d]pyrimidine-7-carbaldehyde
##STR00116##
[0265] To a 50 mL round bottom flask,
4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (3.0 g,
0.0091 mol--Preparation 3) and dry THF (15 mL) were added under
nitrogen atmosphere and then cooled to -78oC. To the reaction
flask, 2.5 M n-butyl lithium (4.4 mL, 0.0109 mol) was slowly added
and the reaction mixture was stirred at -78.degree. C. for 30
minutes. To the reaction mixture, N,N-dimethylformamide (1.27 mL,
0.0164 mol) was added and the reaction mixture allowed to warm to
0.degree. C. The reaction mass was quenched with 10% aqueous
ammonium chloride (100 mL) and extracted with ethyl acetate
(3.times.50 mL). The combined organic layer was washed with brine,
dried over anhydrous sodium sulfate and evaporated to provide the
crude product. The crude product was purified by column
chromatography (60-120 silica gel, 10-40% ethyl acetate) to provide
the title compound as a light yellow solid (0.8 g, 31%). .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. 10.24 (s, 1H), 9.11 (d, J=2.1
Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 3.91 (t, J=4.8 Hz, 8H): LC-MS
(ESI): Calculated mass. 278.06, Observed mass [M+H].sup.+: 279.0
(RT=0.66 min).
Step 2:
1-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)methyl)pip-
erazin-1-yl)-2-hydroxypropan-1-one
##STR00117##
[0267] In a 50 mL round bottom flask,
2-chloro-4-morpholinopyrido[3,2-d]pyrimidine-7-carbaldehyde (0.3 g,
0.0010 mol) and 1,2-dichloroethane (20 mL) were added. To the
reaction flask, 2-hydroxy-1-(piperazin-1-yl)propan-1-one (0.204 g,
0.0013 mol) and trimethyl orthoformate (0.228 g, 0.0030 mol) were
added and the reaction mixture stirred at room temperature for 12
hours. To the reaction mixture, sodium triacetoxyborohydride (g,
0.683 0.0020 mol) was added and stirred at room temperature for 3
hours. The reaction mixture was diluted with DCM, washed with
water, brine, dried over anhydrous sodium sulfate and evaporated
under reduced pressure to provide the crude product. The crude
product was purified by column chromatography (60-12 silica gel, 5%
methanol in chloroform) to provide the title compound (0.15 g,
33%). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 8.62 (d, J=1.8 Hz,
1H), 7.86 (d, J=1.2 Hz, 1H), 4.72 (br s, 4H), 3.84 (t, J=9.0 Hz,
4H), 3.65 (s, 2H), 3.60-3.52 (m, 1H), 3.41 (d, J=2.7 Hz, 1H), 3.23
(s, 4H), 2.46 (d, J=3.0 Hz, 4H), 1.27 (d, J=6.6 Hz, 3H): LC-MS
(ESI): Calculated mass. 420.1, Observed mass [M+H].sup.+: 421.1
(RT=0.24 min).
Step 3:
1-(4-((2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidi-
n-7-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
##STR00118##
[0269] To a 25 mL round bottom flask,
1-(4-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-
-yl)-2-hydroxypropan-1-one (0.1 g, 0.0002 mol),
2-aminopyrimidine-5-boronic acid (0.085 g, 0.0003 mol), cesium
carbonate 0.149 g, 0.0004 mol), DMF (10 mL) and water (3 mL) were
added. The reaction mixture was degassed with N.sub.2 for 5-10
minutes. To the same reaction mixture, Pd(PPh.sub.3).sub.2Cl.sub.2
(0.008 g, 0.00001 mol) was added and degassed with N.sub.2 for 5-10
minutes. The reaction mixture was stirred at 95.degree. C. for 2
hours. The reaction mass was diluted with water and extracted with
ethyl acetate (3.times.25 mL). The combined organic layer was
washed with brine, dried over anhydrous sodium sulfate and
evaporated under reduced pressure to provide the crude product. The
crude product was purified by column chromatography (60-120 silica
gel, 8% methanol in chloroform), followed by preparative HPLC (0.1%
TFA in water and acetonitrile) to provide the title compound (0.007
g, 6%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.18 (s, 2H),
8.82 (s, 1H), 8.25 (s, 1H), 4.72 (br s, 4H), 4.21 (s, 2H),
3.93-3.82 (m, 10H), 3.00 (br s, 4H), 1.33 (d, J=6.4 Hz, 3H): LC-MS
(ESI): Calculated mass. 479.24, Observed mass [M+H].sup.+: 480.2
(RT=0.22 min).
Example 121
((Acetyl(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyrimidin-7-
-yl)phenyl)carbamoyl)oxy)methyl acetate (Scheme VI) (Prodrug of
Example 3)
##STR00119##
[0270] Step 1: Chloromethyl
(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)-carbamate
##STR00120##
[0272] To a 100 mL round bottom flask,
3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)aniline (1.0 g,
0.0029 mol), 1,8-bis(dimethylamino)naphthalene (0.626 g, 0.0029
mol) and chloroform (60 mL) were added. The reaction mixture was
cooled in an ice bath. To the same flask was added chloromethyl
chloroformate (0.377 g, 0.0029 mol) and the mixture was stirred at
room temperature for 3 hours. The reaction mixture was diluted with
chloroform, washed with water and brine. The organic layer was
dried over anhydrous sodium sulphate and evaporated under reduced
pressure to provide the title compound as a yellow solid (1.25 g,
98.4%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 10.41 (br s,
1H), 9.07 (d, J=2.0 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 7.94 (br s,
1H), 7.62-7.51 (m, 3H), 6.01 (s, 2H), 4.98-3.98 (br s, 4H), 3.81
(t, J=4.4 Hz, 4H). LC-MS (ESI): Calculated mass: 433.07; Observed
mass [M+H].sup.+: 433.8 (RT: 1.63 min).
Step 2:
(((3-(2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)carb-
amoyl)oxy)-methyl acetate
##STR00121##
[0274] To a 100 mL round bottom flask,
chloromethyl(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)c-
arbamate (1.2 g, 0.0028 mol) and acetic acid (20 mL) were added. To
the reaction mixture was added mercuric acetate (0.968 g, 0.0031
mol) and the mixture was stirred at room temperature for 4 hours.
The reaction mixture was diluted with chloroform and washed with
water. The organic layer was washed with brine, dried over
anhydrous sodium sulphate and evaporated under reduced pressure to
provide the title compound as a yellow solid (1.1 g, 87%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 10.25 (br s, 1H), 9.05 (d,
J=1.6 Hz, 1H), 8.19 (d, J=1.2 Hz, 1H), 7.93 (s, 1H), 7.59-7.48 (m,
3H), 5.77 (s, 2H), 4.64-3.98 (br s, 4H), 3.81 (t, J=4.4 Hz, 4H),
2.10 (s, 3H). LC-MS (ESI): Calculated mass: 457.12; Observed mass
[M+H].sup.+: 457.9 (RT: 1.57 min).
Step 3:
((Acetyl(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)pheny-
l)-carbamoyl)-oxy)methyl acetate
##STR00122##
[0276] To a 100 mL round bottom flask,
(((3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)carbamoyl)o-
xy)methyl acetate (1.0 g, 0.0022 mol), triethylamine (0.6 mL,
0.0044 mol) N,N-dimethylpyridin-4-amine (0.0054 g, 0.000044 mol)
and DCM (25 mL) were added. To the same flask was added acetic
anhydride (2.67 g, 0.0264 mol). The reaction was continued at room
temperature for 18 hour. Additional acetic anhydride (1.63 g,
0.0161 mol) was then added to the reaction mixture. The reaction
was further continued at room temperature for 24 hours. The
reaction mixture was diluted with DCM. The organic layer was washed
with water, brine, dried over anhydrous sodium sulphate and
evaporated under reduced pressure to provide the title compound
(0.97 g, 83%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.14
(d, J=2.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H),
7.87 (s, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.53 (dd, J'=7.6 Hz, J''=0.8
Hz, 1H), 5.66 (s, 2H), 4.65-3.97 (br s, 4H), 3.80 (t, J=4.8 Hz,
4H), 2.55 (s, 3H), 2.03 (s, 3H). LC-MS (ESI): Calculated mass:
499.13; Observed mass [M+H].sup.+: 499.8 (RT: 1.52 min).
Step 4:
((Acetyl(3-(2-(2-aminopyrimidin-5-yl)-4-morpholinopyrido[3,2-d]pyr-
imidin-7-yl)-phenyl)carbamoyl)oxy)methyl acetate
##STR00123##
[0278] To a 50 mL sealed tube,
((acetyl(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)carba-
moyl)oxy)methyl acetate (0.96 g, 0.0019 mol),
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine
(0.852 g, 0.0038 mol), potassium phosphate tribasic (0.81 g, 0.0038
mol), 1,4-dioxane (45 mL), and water (4 mL) were added. The
reaction mixture was degassed with N.sub.2 for 5-10 minutes. To the
same reaction mixture, Pd(PPh.sub.3).sub.4 (0.11 g, 0.000096 mol)
was added and the mixture was degassed with N.sub.2 for 5-10 min.
The reaction mixture was stirred at 82.degree. C. for 30 minutes.
The volatiles were evaporated to provide a residue. The residue was
dissolved in chloroform. The chloroform layer was washed with
water, brine, dried over anhydrous sodium sulphate and evaporated
under reduced pressure to provide a crude solid. The crude solid
was purified by flash column chromatography (0-2% methanol in
chloroform) to provide a solid. The solid was washed with methanol
to provide the title compound as a light yellow solid (0.4 g, 40%).
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 9.18 (s, 2H), 9.08 (s,
1H), 8.35 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.91 (br s, 1H), 7.62
(t, J=7.6 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.20 (br s, 2H), 5.68
(s, 2H), 4.52 (br s, 4H), 3.84 (t, J=4.0 Hz, 4H), 2.57 (s, 3H),
2.06 (s, 3H). LC-MS (ESI): Calculated mass: 558.20; Observed mass
[M+H].sup.+: 558.8 (RT: 0.40 min).
Examples 1 to 126
[0279] Additional compounds listed in Table 1 were prepared in a
similar manner, using the methods described for Examples 1 to 11
and in the Schemes I to VI. In some cases, compounds were isolated
and characterized as the trifluoroacetate or hydrochloride salt.
LC-MS characterization data for Examples 1 to 126 are tabulated in
Table 2. Further additional compounds of the invention are prepared
in a similar manner to the methods described for the Examples 1 to
126 and in Schemes I to VI.
TABLE-US-00001 TABLE 1 Ex. Synthetic No. Structure Structure Name
Method 1 ##STR00124## 5-(7-(3 (methyl- sulfonyl)phenyl)-4-
morpholinoquinazolin-2- yl)pyrimidin-2-amine I 2 ##STR00125##
5-(6-fluoro-7-(3- (methylsulfonyl)phenyl)- 4-morpholinoquinazolin-
2-yl)pyrimidin-2-amine I 3 ##STR00126## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2-d]- pyrimidin-7-yl)phenyl)-
acetamide II 4 ##STR00127## 4-(2-(2-aminopyrimidin-
5-yl)-4-morpholino- pyrido[3,2-d]pyrimidin-7- yl)-N-cyclopropyl-
benzamide III 5 ##STR00128## (5-(2-(2-aminopyrimidin- 5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)furan-2-
yl)(4-methylpiperazin-1- yl)methanone III 6 ##STR00129##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinoquinazolin-7-
yl)phenyl)-2-hydroxy-2- methylpropanamide IVa 7 ##STR00130##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)- phenyl)cyclopropane- carboxamide IVa 8
##STR00131## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)- 4-fluoro-
benzenesulfonamide IVb 9 ##STR00132## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2-d]-
pyrimidin-7-yl)phenyl)-2- (4-hydroxypiperidin-1- yl)acetamide IVc
10 ##STR00133## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)- phenyl)morpholine-4-
carboxamide IVd 11 ##STR00134## 1-(4-((2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-
methyl)piperazin-1-yl)-2- hydroxypropan-1-one V 12 ##STR00135##
5-(4-morpholino-7- (pyrimidin-5- yl)quinazolin-2-
yl)pyrimidin-2-amine I 13 ##STR00136## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinoquinazolin-7- yl)phenyl)acetamide I 14
##STR00137## 5-(7-(1-methyl-1H- pyrazol-4-yl)-4-
morpholinoquinazolin-2- yl)pyrimidin-2-amine I 15 ##STR00138##
1-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinoquinazolin-7-
yl)phenyl)-3-methylurea I 16 ##STR00139## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinoquinazolin-7- yl)phenyl)methane-
sulfonamide I 17 ##STR00140## 5-(4-morpholino-7- (thiophen-3-yl)-
quinazolin-2-yl)- pyrimidin-2-amine I 18 ##STR00141##
5-(7-(5-(methyl- sulfonyl)pyridin-3-yl)-4- morpholinoquinazolin-2-
yl)pyrimidin-2-amine I 19 ##STR00142## 5-(7-(2-fluoropyridin-3-
yl)-4-morpholino- quinazolin-2-yl)- pyrimidin-2-amine I 20
##STR00143## 5-(7-(3-(methyl- sulfonyl)phenyl)-4-
morpholinopyrido[3,2-d]- pyrimidin-2-yl)pyrimidin- 2-amine II 21
##STR00144## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2-d]- pyrimidin-7-yl)phenyl)- methanesulfonamide
II 22 ##STR00145## 5-(7-(1-methyl-1H- pyrazol-4-yl)-4-
morpholinopyrido[3,2-d]- pyrimidin-2-yl)pyrimidin- 2-amine II 23
##STR00146## 5-(4-morpholino-7- (pyrimidin-5-yl)-
pyrido[3,2-d]pyrimidin-2- yl)pyrimidin-2-amine II 24 ##STR00147##
5-(7-(2-fluoropyridin-3- yl)-4-morpholino-
pyrido[3,2-d]pyrimidin-2- yl)pyrimidin-2-amine II 25 ##STR00148##
5-(7-(furan-2-yl)-4- morpholinopyrido[3,2-d]-
pyrimidin-2-yl)pyrimidin- 2-amine II 26 ##STR00149##
5-(7-(5-methylfuran-2- yl)-4-morpholino- pyrido[3,2-d]pyrimidin-2-
yl)pyrimidin-2-amine II 27 ##STR00150## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2-d]- pyrimidin-7-yl)phenyl)-
N-methylacetamide II 28 ##STR00151## 1-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
3-methylurea II 29 ##STR00152## 1-(4-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
3-methylurea II 30 ##STR00153## N-(5-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)pyridin-
3-yl)acetamide II 31 ##STR00154## N-(5-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)pyridin-
3-yl)cyclopropane- carboxamide II 32 ##STR00155## N-(4-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-3-
fluorophenyl)cyclo- propanecarboxamide II 33 ##STR00156##
4-(2-(2-aminopyrimidin- 5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)-N- methylbenzamide III 34 ##STR00157##
5-(2-(2-aminopyrimidin- 5-yl)-4-morpholino-
pyrido[3,2-d]pyrimidin-7- yl)-N-(pyridin-3-yl)furan- 2-carboxamide
III 35 ##STR00158## 1-(4-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2-d]- pyrimidin-7-yl)benzoyl)-
piperazin-1-yl)ethanone III 36 ##STR00159##
(3-(2-(2-aminopyrimidin- 5-yl)-4-morpholino-
pyrido[3,2-d]pyrimidin-7- yl)phenyl)(4-(methyl-
sulfonyl)piperazin-1-yl)- methanone III 37 ##STR00160##
4-(2-(2-aminopyrimidin- 5-yl)-4-morpholino-
pyrido[3,2-d]pyrimidin-7- yl)-N-(thiazol-2-yl)- benzamide III 38
##STR00161## 4-(2-(2-aminopyrimidin- 5-yl)-4-morpholino-
pyrido[3,2-d]pyrimidin-7- yl)-N-(pyridin-4-yl)- benzamide III 39
##STR00162## (4-(2-(2-aminopyrimidin- 5-yl)-4-morpholino-
pyrido[3,2-d]pyrimidin-7- yl)phenyl)(4-hydroxy-
piperidin-1-yl)methanone III 40 ##STR00163##
(3-(2-(2-aminopyrimidin- 5-yl)-4-morpholino-
pyrido[3,2-d]pyrimidin-7- yl)phenyl)(4-hydroxy-
piperidin-1-yl)methanone III 41 ##STR00164##
3-(2-(2-aminopyrimidin- 5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)-N,N- dimethylbenzamide III 42 ##STR00165##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinoquinazolin-7-
yl)phenyl)-2- (dimethylamino)- acetamide IVa 43 ##STR00166##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinoquinazolin-7-
yl)phenyl)-2-hydroxy- propanamide IVa 44 ##STR00167##
(S)-N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinoquinazolin-7-
yl)phenyl-2-hydroxy- propanamide IVa 45 ##STR00168##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)phenyl)- 2-hydroxypropanamide IVa 46 ##STR00169##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)phenyl)- 2-(dimethylamino)- acetamide IVa 47
##STR00170## (S)-N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
2-hydroxypropanamide IVa 48 ##STR00171## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
2-hydroxy-2- methylpropanamide IVa 49 ##STR00172##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)phenyl)- 2-cyano-2- methylpropanamide IVa 50
##STR00173## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)- 2-hydroxyacetamide
IVa 51 ##STR00174## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)- 2-fluoropropanamide
IVa 52 ##STR00175## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)-2- fluorophenyl)acetamide
IVa 53 ##STR00176## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)- 2-cyanoacetamide
IVa 54 ##STR00177## N-(4-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)- phenyl)acetamide IVa 55
##STR00178## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)-4- fluorophenyl)acetamide
IVa 56 ##STR00179## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)-2- methylphenyl)acetamide
IVa 57 ##STR00180## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)- phenyl)cyclopentane-
carboxamide IVa 58 ##STR00181## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-
phenyl)nicotinamide IVa 59 ##STR00182## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
5-methylfuran-2- carboxamide IVa 60 ##STR00183## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-
phenyl)cyclohexane- carboxamide IVa 61 ##STR00184##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)phenyl)- 1-cyanocyclopropane- carboxamide IVa 62
##STR00185## N-(4-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)- phenyl)cyclopropane-
carboxamide IVa 63 ##STR00186## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-
phenyl)tetrahydro-2H- pyran-4-carboxamide IVa 64 ##STR00187##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)- phenyl)pyrazine-2- carboxamide IVa 65
##STR00188## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)- phenyl)adamantane-1-
carboxamide IVa 66 ##STR00189## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
4-methylpentanamide IVa 67 ##STR00190## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-
phenyl)furan-2- carboxamide IVa 68 ##STR00191## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
4-(trifluoromethyl)- nicotinamide IVa 69 ##STR00192##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)phenyl)- 1,2,3-thiadiazole-4- carboxamide IVa 70
##STR00193## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
4-hydroxycyclohexane- carboxamide IVa 71 ##STR00194##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-d]-
pyrimidin-7-yl)-4-fluoro- phenyl)nicotinamide IVa 72 ##STR00195##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)-4- fluorophenyl)-5- methylfuran-2- carboxamide
IVa 73 ##STR00196## N-(4-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)- 5-methylfuran-2-
carboxamide IVa 74 ##STR00197## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
4-fluorobenzamide IVa 75 ##STR00198## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
3-methyl-1H-pyrazole-5- carboxamide IVa 76 ##STR00199##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)- phenyl)cyclobutane- carboxamide IVa 77
##STR00200## N-(4-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)- phenyl)nicotinamide IVa 78
##STR00201## N-(4-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)- phenyl)cyclobutane-
carboxamide IVa 79 ##STR00202## N-(4-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-
phenyl)furan-2- carboxamide IVa 80 ##STR00203## N-(4-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
3-methyl-1H-pyrazole-5- carboxamide IVa 81 ##STR00204##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)- phenyl)cyclopropane- sulfonamide IVb 82
##STR00205## N-(4-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2-d]- pyrimidin-7-yl)phenyl)-
cyclopropanesulfonamide IVb 83 ##STR00206## N-(3-(2-(2-
aminopyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)phenyl)- 2-(4-methylpiperazin-1- yl)acetamide IVc
84 ##STR00207## N-(3-(2-(2- aminopyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)phenyl)-
2-morpholinoacetamide IVc 85 ##STR00208## N-(3-(2-(2-
aminopyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-4-
fluorophenyl)-2-(4- methylpiperazin-1-yl)- acetamide IVc 86
##STR00209## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2-d]- pyrimidin-7-yl)-2-fluoro-
phenyl)-2-(4-methyl- piperazin-1-yl)acetamide IVc 87 ##STR00210##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinoquinazolin-7-
yl)phenyl)-4-methyl- piperazine-1-carboxamide IVd 88 ##STR00211##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinoquinazolin-7-
yl)phenyl)morpholine-4- carboxamide IVd 89 ##STR00212## N-(3-(2-(2-
aminopyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)phenyl)- 4-methylpiperazine-1- carboxamide IVd 90
##STR00213## 1-(4-((2-(2- aminopyrimidin-5-yl)-4-
morpholinoquinazolin-7- yl)methyl)piperazin-1-
yl)-2-hydroxypropan-1- one V 91 ##STR00214## 1-(4-((2-(2-amino-
pyrimidin-5-yl)-4- morpholinoquinazolin-7- yl)methyl)piperazin-1-
yl)-2-hydroxy-2-methyl- propan-1-one V 92 ##STR00215##
1-(4-((2-(2-amino- pyrimidin-5-yl)-4- morpholinoquinazolin-7-
yl)methyl)piperazin-1- yl)ethanone V 93 ##STR00216##
N-(1-((2-(2-amino- pyrimidin-5-yl)-4- morpholinoquinazolin-7-
yl)methyl)piperidin-4-yl)- acetamide V 94 ##STR00217##
5-(4-morpholino-7- (piperazin-1-yl- methyl)pyrido[3,2-d]-
pyrimidin-2-yl)pyrimidin- 2-amine V 95 ##STR00218##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-d]-
pyrimidin-7-yl)-4- fluorophenyl)cyclopropane- carboxamide II 96
##STR00219## N-(5-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2-d]- pyrimidin-7-yl)pyridin-3-
yl)methanesulfonamide II 97 ##STR00220## 3-(2-(2-aminopyrimidin-
5-yl)-4- morpholinopyrido[3,2-d]- pyrimidin-7-yl)-N-(3-
fluoropyridin-4-yl)- benzamide III 98 ##STR00221##
3-(2-(2-aminopyrimidin- 5-yl)-4- morpholinopyrido[3,2-d]-
pyrimidin-7-yl)-N- cyclopropylbenzamide III 99 ##STR00222##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-d]-
pyrimidin-7-yl)phenyl)-5- fluoronicotinamide IVa 100 ##STR00223##
5-(7-(5-(4-methyl- piperazin-1-yl)pyridin-3- yl)-4-morpholino-
pyrido[3,2-d]pyrimidin-2- yl)pyrimidin-2-amine II 101 ##STR00224##
5-(7-(3-(4-methyl- piperazin-1-yl)phenyl)-4-
morpholinopyrido[3,2-d]- pyrimidin-2-yl)pyrimidin- 2-amine II 102
##STR00225## 3-(2-(2-aminopyrimidin- 5-yl)-4-
morpholinopyrido[3,2-d]- pyrimidin-7-yl)-N-(2-
(dimethylamino)ethyl)- benzamide III 103 ##STR00226##
3-(2-(2-aminopyrimidin- 5-yl)-4- morpholinopyrido[3,2-d]-
pyrimidin-7-yl)-N- methylbenzamide III 104 ##STR00227##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-d]-
pyrimidin-7-yl)- phenyl)propionamide IVa 105 ##STR00228##
N-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-d]-
pyrimidin-7-yl)- phenyl)isobutyramide IVa 106 ##STR00229##
5-(4-morpholino-7-(3- (piperazin-1-yl)- phenyl)pyrido[3,2-d]-
pyrimidin-2-yl)pyrimidin- 2-amine II 107 ##STR00230##
3-(4-(3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-d]-
pyrimidin-7-yl)- phenyl)piperazin-1-yl)- 2,2-dimethyl-3-
oxopropanenitrile IVa 108 ##STR00231## 1-(4-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-
phenyl)piperazin-1-yl)-2- hydroxy-2-methylpropan- 1-one IVa 109
##STR00232## 2-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)- phenyl)propan-2-ol III 110
##STR00233## (3-(2-(2-aminopyrimidin- 5-yl)-4-
morpholinopyrido[3,2-d]- pyrimidin-7-yl)phenyl)(4-
methylpiperazin-1-yl)- methanone III 111 ##STR00234##
6-(2-(2-aminopyrimidin- 5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)-2H- benzo[b][1,4]oxazin- 3(4H)-one II 112
##STR00235## 1-(4-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)- phenyl)piperazin-1-yl)-2-
(dimethylamino)ethanone IVa 113 ##STR00236## 2-(4-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-
phenyl)piperazin-1-yl)- ethanol II 114 ##STR00237##
N-(5-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)-2-(4- methylpiperazin-1-yl)- phenyl)acetamide II
115 ##STR00238## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)-2- fluorophenyl)-
cyclopropane- carboxamide IVa 116 ##STR00239##
(3-(2-(2-aminopyrimidin- 5-yl)-4- morpholinopyrido[3,2-d]-
pyrimidin-7-yl)phenyl)(4- (2- hydroxyethyl)piperazin-
1-yl)methanone III 117 ##STR00240## N-(5-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-2-(4-
methylpiperazin-1-yl)- phenyl)cyclopropane- carboxamide II 118
##STR00241## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)- phenyl)pivalamide IVa 119
##STR00242## N-(5-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2-d]- pyrimidin-7-yl)-2- fluorophenyl)acetamide
II 120 ##STR00243## 1-((acetyl(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2-d]- pyrimidin-7-yl)- phenyl)carbamoyl)oxy)
ethyl acetate VI 121 ##STR00244## ((acetyl(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2-d]- pyrimidin-7-yl)-
phenyl)carbamoyl)oxy) methyl acetate VI 122 ##STR00245##
(((3-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)- phenyl)(cyclopropane- carbonyl)carbamoyl)-
oxy)methyl acetate VI 123 ##STR00246## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-2,4-
difluorophenyl)acetamide IVa 124 ##STR00247## N-(3-(2-(2-amino-
pyrimidin-5-yl)-4- morpholinopyrido[3,2- d]pyrimidin-7-yl)-4-
fluorophenyl)-1- cyanocyclopropane- carboxamide IVa 125
##STR00248## N-(3-(2-(2-amino- pyrimidin-5-yl)-4-
morpholinopyrido[3,2- d]pyrimidin-7-yl)-2- fluorophenyl)-1-
cyanocyclopropane- carboxamide IVa 126 ##STR00249##
N-(5-(2-(2-amino- pyrimidin-5-yl)-4- morpholinopyrido[3,2-
d]pyrimidin-7-yl)-2- fluorophenyl)- cyclopropane carboxamide IVa
##STR00250##
Example 127
Biological Assays
(i) PI3 Kinase Time-Resolved Fluorescence Resonance Energy Transfer
(TR-FRET) Assay
[0280] The ability of compounds of the invention to inhibit PI3K
activity was determined in a homogeneous TR-FRET assay using a PI3K
assay kit (Millipore, USA; cat #33-016) according to manufacturer's
instructions. PI3-Kinases (isoforms .alpha., .beta., .gamma. and
.delta.) catalyze the phosphorylation of phosphatidylinositol, PIP2
to PIP3 in the presence of ATP and Mg.sup.2+. The PIP3 product is
detected by displacement of biotin-PIP3 from an energy transfer
complex consisting of Europium labeled anti-GST monoclonal
antibody, a GST-tagged PH domain, biotinylated PIP3 and
Streptavidin-APC. Excitation of Europium in the complex results in
an energy transfer to the APC and a fluorescence emission at 665
nm. The PIP3 product displaces biotin-PIP3 from the complex
resulting in a loss of energy transfer and thus a decrease in
signal.
[0281] To test for the ability of compounds to inhibit the activity
of PI3K.alpha. (wild-type), exemplary compounds of formula (I) were
dissolved in DMSO and directly distributed into 384-well plates at
a volume of 0.5 .mu.L. 14.5 .mu.L of P110/P85.alpha./PIP2 mixture
in buffer (obtained from the Millipore kit) containing MgCl.sub.2
(40 mM) and DTT (5 mM) was added to compound wells and incubated
for 60 minutes at room temperature. P110/P85.alpha. was expressed
in SF9 insect cells and purified nickel column extraction. Five ng
of wild-type P110/P85.alpha. was used in the assay. The kinase
reaction was started by the addition of ATP. The assay
concentrations of both PIP2 and ATP were 10 .mu.M. The reaction
mixture was incubated for 30 minutes at room temperature and was
terminated by the addition of stop mix and detection mix.
Fluorescence was measured at 615 and 665 nm upon excitation at 340
nm in a Victor.TM. V5 fluorometer (Perkin Elmer, USA). The
fluorescence emission ratio at 665 to 615 nm, proportional to the
kinase activity, was plotted against the compound concentration to
generate dose-response curves and IC.sub.50 values were determined
using GraphPad Prism.RTM. 5 software.
[0282] Inhibition of PI3K.alpha. activity was observed for
compounds of formula (I) as determined by this assay. See, Table
2.
[0283] The activity of PI3 kinase isoforms .beta., .gamma. and
.delta. were assayed in a similar manner to the assay protocol
described above for PI3K.alpha., by substituting the appropriate
p110/p85 isoform for the p110.alpha./p85.alpha.. Compounds of
formula (I) caused inhibition of PI3 kinase isoforms .beta.,
.gamma. and .delta. as determined by these assays. For example, the
compounds of Examples 3 and 21 each caused inhibition of PI3 kinase
isoform .beta. with IC50 values<500 nM. The compounds of
Examples 3, 7, 21, 47, 48 and 49 each caused inhibition of PI3
kinase isoform .gamma. with IC50 values<500 nM. The compounds of
Example 3, 7, 47, 48, and 49 caused inhibition of PI3 kinase
isoform .delta. with IC50 values<1 .mu.M.
[0284] The activity of PI3K.alpha. mutations H1047R and E545K were
assayed in a similar manner to the assay protocol described above
for PI3K.alpha. (wild type). The compounds of formula (I) caused
inhibition of PI3K.alpha. mutations H1047R (a mutation associated
with breast and gastric cancers) and E545K (a mutation associated
with colorectal tumors, glioblastomas, gastric cancers, breast
cancers, and lung cancers). For example, each of the compounds of
Example 3, 7, 21, 47, 48 and 49 caused inhibition of each of the
PI3K.alpha. mutations H1047R and E545K with IC50 values<50
nM.
(ii) mTOR Kinase TR-FRET Assay
[0285] Compound inhibition for mTOR kinase was determined in a
homogeneous TR-FRET assay using the Lance.RTM. ULight-p70 S6K (Thr
389) peptide (obtained from Perkin-Elmer). The ULight.TM.-labeled
synthetic peptide contains the amino acid residues surrounding
Thr389 of human p70 S6K. The ULight-p70 S6K peptide is
phosphorylated at Thr389 by mTOR. Phosphorylation motif: LGFTYVAP
as substrate.
[0286] The compound dilution was carried out in 100% DMSO followed
by a buffer dilution. The reaction buffer was HEPES (50 mM pH 7.5),
EGTA (1 mM), MnCl.sub.2 (3 mM). Test compounds at various
concentrations were pre-incubated with mTOR (Millipore, USA; 5 ng)
for 60 min, and then the Lance.RTM. ULight-p70 S6K (Thr 389)
peptide (50 nM) was added along with ATP (20 .mu.M). After
incubating the reaction mixture for 60 minutes at room temperature,
the kinase reaction was terminated by the addition of EDTA (10 mM)
followed by the addition of detection mix, i.e., 1 nM Eu-labeled
anti-phospho-substrate antibody (Perkin Elmer, USA). The
fluorescence emission at 615 and 665 nM was measured upon
excitation at 340 nM. IC.sub.50 values were subsequently determined
using a sigmoidal dose-response curve (variable slope) in GraphPad
Prism.RTM. 5 software.
[0287] Compounds of formula (I) caused inhibition of mTOR kinase
activity as determined by this assay. See Table 2.
(iii) In-Cell Western Assay
[0288] Cells from human prostate cancer cell line PC3 (American
Type Culture Collection (ATCC), Manassas, Va. 20108 USA) were
seeded at an optimal density of 22,000 cell/well in 96-well plates
containing Ham's F12K medium (90 .mu.L) and incubated overnight.
The compound dilutions were carried out in 100% DMSO followed by a
dilution in the medium. Test compounds were added in serial
dilutions to the wells and incubated for 2 hours. The cells were
washed and fixed with 4% paraformaldehyde. After incubation at room
temperature for 1 hour in the dark, blocking was done for 2 hours
at room temperature. Primary antibodies for pAkt(S473) (Aid
phosphorylated at serine 473), pAkt(T308) (Akt phosphorylated at
threonine 308) and for pS6RP (S235/236) (phosphorylated at serine
235/236) (commercially available from Cell Signaling
Technology.RTM., whose protocol was followed for the in-cell
western assay, were diluted to the required concentration and added
to the corresponding wells followed by overnight incubation at
4.degree. C. Eu-labeled rabbit (PE) (Perkin-Elmer USA catalog
#AD0106) secondary antibody was added and incubated for 2 hours at
room temperature. Delfia.RTM. enhancement solution (cat #1244-105,
Perkin Elmer USA) was subsequently added to the plate before taking
the reading at 615 nm with excitation wavelength of 340 nm, after
which 0.5 .mu.g/mL of Hoechst.RTM. 33258 dye (Catalog #86140-5,
Sigma) was added to the plate and fluorescence emission was read at
460 nm with 355 nm excitation, to evaluate the correction factor.
IC.sub.50 values were calculated using a sigmoidal dose-response
curve fit in GraphPad Prism.RTM. v5 software. Compounds of formula
(I) inhibited phosphorylation of Akt(S473), Akt(T308) and S6RP in
PC3 cells, as shown in Table 2. These results indicate the ability
of the tested compounds to inhibit a PI3K/Akt-pathway dependent
prostate neoplasm.
[0289] In-cell Western assays for pAkt(T308) and pS6RP were also
carried out in a glioma cancer cell line with a PTEN null mutation
(U87MG cells), in a similar manner to the protocol described above
for PC3 cells, in order to assess the ability of the compounds to
inhibit the Akt-pathway in a glioma cancer cell line. The compound
of Example 3 caused inhibition of pAkt(T308) and pS6RP in U87MG
cells with IC50 values<500 nM. In-cell Western assays for
pAkt(T308), pAkt(S473) and pS6RP are also carried out in a breast
cancer cell line with PI3K mutations (PIK3CA-K111N mutation) which
overexpresses HER 2 (BT474 cells) and a human ductal breast
epithelial cell line with PI3K mutations (PIK3CA-H1047R mutation)
(T47D cells), in a similar manner to the protocol described above
for PC3 cells, in order to assess the ability of the compounds to
inhibit the Akt-pathway in two breast cancer cell lines. Compounds
of the invention cause inhibition of pAkt(T308), pAkt(S473) and
pS6RP in U87MG, BT474 and T47D cell lines as determined by these
assays.
(iv) XTT Assay for Cell Viability
[0290] Using a commercial kit from Sigma Aldrich (Catalog #X34251)
and following its protocol, PC3 cells in the log phase of growth
were employed and seeded at an optimal density of 1000 cell/well on
to 96 well plates and incubated for 24 hours followed by the
addition of compounds of formula (I) in serial dilutions. Compound
dilutions were made in DMSO. The cells were incubated with the
compounds of formula (I) for 96 hours and XTT tetrazolium dye
(Sigma, USA) was subsequently added and incubated at 37.degree. C.
After the color formation, absorbance was measured at 465 nm in a
Spectramax.RTM. Gemini spectrophotometer. EC.sub.50 values were
calculated using a sigmoidal dose response curve fit in GraphPad
Prism.RTM. v5 software. The tested compounds of formula (I) which
caused inhibition of PC3 cell proliferation as determined by this
assay protocol are shown in Table 2.
[0291] XTT assays for cell viability were also determined in U87MG,
BT474 cells and T47D cells, in a similar manner to the protocol
described above. The compounds cause inhibition of U87MG, BT474 and
T47D cell proliferation as determined by these assays. For example,
the compounds of Examples 3 and 7 caused inhibition of U87MG, BT474
and T47D cell proliferation with IC50 values<600 nM.
(v) In Vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Studies for
Oncology
[0292] PC3 cells are cultured at 37.degree. C. in a 5% CO.sub.2
incubator using Hams F12 K medium. Ten million (10.sup.7) cells are
injected subcutaneously to the right flank region of athymic male
mice (Harlan, age: 6-7 weeks, weight: about 20 g). Tumor bearing
mice are randomized when the tumor volume reaches about 250
mm.sup.3 and three mice are used per each time point. Test
compounds of formula (I) are typically formulated in 40% HPCD in
1.times.PBS, pH 7.4 or in 10% Ethanol/40% Solutol/50% 50 mM aq.
methanesulfonic acid and dosed orally at 50 mg/kg single dose (dose
volume--10 mL/kg). Plasma and tumor samples are collected at 0
(vehicle control animals), 1, 4 and 24 hours post dosing. Blood is
drawn (retro orbital) to a tube containing 0.2% EDTA for plasma
collection. The tumor is excised from the mouse and immediately
frozen in liquid nitrogen for PD analysis. Tumor and plasma drug
concentrations are measured for PK analysis using LC-MS.
[0293] Snap frozen tumor samples are pulverized in a mortar
(Belart) containing liquid nitrogen and tumor powder is stored at
-80.degree. C. until analysis. Pre coated ELISA kits (Cell
Signaling Technology; pAKT (T308), CST#7135; pAKT (S473), CST#7134
and pS6RP, CST#7205) are used for PD analysis. Tumor powder is
transferred to Eppendorf.RTM. tubes and lysis buffer (1 mL) is
added to the powder. Protease and phosphatase inhibitors (SIGMA)
and phenylmethane-sulfonylfluoride (PMSF) are added to tumor powder
and mixed by vortexing followed by sonication (15 sec). Samples are
kept on an ice bath for 30 minutes. Supernatant is separated after
centrifugation at 10,000 rpm for 20 minutes at 4.degree. C.
Supernatant is re-centrifuged and fresh supernatant is aliquoted to
different tubes. Total protein is estimated using a BCA kit (Thermo
Scientific) and 50 .mu.g total protein is loaded to each well.
ELISA analysis is carried out as per manufacturer's instructions.
The detection for pAKT is based on chemiluminescence and pS6RP is
based on absorbance. Qualitative assessments of the suppression of
pAKT (T308), pAKT (S473), and pS6RP are also carried out by
standard Western blot analyses.
[0294] The compounds cause suppression of pAkt and pS6RP as
measured at 1, 4 and 24 hours after a single dose of 30-50 mg/kg
po.
[0295] In vivo pharmacokinetic/pharmacodynamic (PK/PD) studies were
carried out in a similar manner using U87MG tumor cells (glioma
cancer cell line with a PTEN null mutation) and the corresponding
tumor-bearing xenograft mice, and compounds of the invention were
determined to be active in this assay. For example, the compound of
Examples 3 and 61 were determined to cause suppression of pAKT
(T308), pAKT (S473), and pS6RP, when dosed at 50 mg/kg po.
(vi) In Vivo Efficacy Studies for Oncology (Tumor Growth
Suppression)
[0296] PC3 cells were cultured at 37.degree. C. in a 5% CO.sub.2
incubator using Hams F12 K medium. Five million (5.times.10.sup.6)
cells were implanted subcutaneously to the right flank of athymic
male mice (Harlan, age: 6-7 weeks, weight: about 20 g). Tumor
bearing mice were randomized when the tumor volume reached about
100 mm.sup.3 Ten mice were used per group. Compounds of formula (I)
were typically formulated using HPCD in PBS, pH 7.4 or in 10%
Ethanol/40% Solutol/50% 50 mM aq. methanesulfonic acid and dosed
orally (dose volume, 10 mL/kg). Solutions of the compounds were
prepared immediately before dosing the animals. A vehicle control
and a reference compound were included along with test
compounds.
[0297] The tumor size was measured on alternate days using
Vernier.RTM. calipers. Assuming tumors to be ellipsoid, the tumor
volume was calculated using the formula:
V=(D.times.d.sup.2)/2 [0298] where: [0299] V (mm.sup.3) is tumor
volume [0300] D is longest diameter in mm [0301] d is shortest
diameter in mm.
[0302] Changes in tumor volume (.DELTA. volumes) for each treated
(T) and control (C) group were calculated by subtracting the mean
tumor volume on the first day of treatment (starting day) from the
mean tumor volume on the specified observation day. These values
were used to calculate a percentage growth (% T/C) using the
formula:
% T/C=(.DELTA.T/.DELTA.C).times.100
[0303] where .DELTA.T>0, or
% T/C=(.DELTA.T/.DELTA.Ti).times.100
[0304] where .DELTA.T<0 and Ti is the mean tumor volume at the
start of the experiment.
[0305] Percentage tumor growth inhibition was calculated as [100-%
T/C]. Percentage body weight change was calculated as [(Body weight
on specified observation day-Body weight on starting day)/Body
weight on starting day].times.100. Compounds of the invention
suppress tumor growth in this in vivo efficacy model. For example,
the compound of Example 3 caused more than 40% tumor growth
inhibition as measured relative to vehicle control group, after 14
days of dosing at 50 mg/kg qd po.
[0306] In vivo efficacy studies were also carried out using U87MG
tumor cells, in a similar manner to the protocol described above
for the PC3 tumor cell in vivo efficacy study. Compounds of the
invention suppressed tumor growth in the in vivo U87MG efficacy
model. For example, relative to vehicle control group after 12 to
14 days of dosing, the compound of Examples 3, 7, 61, 105 and 119
at 50 mg/kg qd po caused more than 80% tumor growth inhibition, and
the compound of Example 120 at 50 mg/kg qd po caused more than 70%
tumor growth inhibition. It should be noted that the compound of
Example 120 is a prodrug of the compound of Example 3.
(vii) In Vivo Efficacy Studies for Inflammation
[0307] The ability of compounds of the invention to reduce
inflammation is determined by using various animal models that are
known in the art. Some examples are as follows:
[0308] (a) Inflammatory arthritis. The ability of compounds of the
invention to reduce inflammation in inflammatory arthritis is
determined by following procedures for the collagen-induced
arthritis (CIA) mouse model. See, e.g., the procedure described in
Camps et al., Nature Med. 2005, 11, 936-943, which is incorporated
herein by reference.
[0309] (b) Pulmonary fibrosis. The ability of compounds of the
invention to prevent bleomycin-induced pulmonary fibrosis in rats
is determined by following the procedures described in Wei et al.,
Biochem. Biophys. Res. Comm. 2010, 397, 311-317 and Brent et al.,
Toxicology 2000, 147, 1-13, which are incorporated herein by
reference.
[0310] (c) Myocardial infarction. The ability of compounds of the
invention to reduce inflammation and/or improve healing after
myocardial infarction is determined by following the procedures for
a mouse model described in Siragusa et al., Circ. Res. 2010, 106,
757-768, which is incorporated herein by reference.
[0311] (d) Peritonitis. The ability of compounds of the invention
to reduce inflammation in peritonitis is determined by following
procedures for the RANTES-induced or thioglycollate-induced
peritonitis mouse model, e.g., as described in Camps et al., Nature
Med. 2005, 11, 936-943, which is incorporated herein by
reference.
TABLE-US-00002 TABLE 2 LC-MS and Biological Data of Examples 1 to
126 LC- LC- MS MS m/z Ret. Ex. [M + time pAkt- pAkt- No. H].sup.+
(min) PI3K.alpha. mTOR T308 S473 pS6RP XTT 1 463.1 0.23 B B F E E F
2 481.1 0.30 A B F F 3 443.1 0.18 A A E E E E 4 469.0 0.19 A A D 5
502.0 0.08 A B E 6 486.2 0.11 B B 7 469.1 0.35 A A E D E E 8 558.9
1.19 A A E F 9 542.3 0.10 A A D E 10 514.2 0.19 A A F 11 480.2 0.22
C C 12 387.1 0.22 C C 13 442.0 0.23 C B F 14 389.1 0.22 C C F 15
457.2 0.23 C A F 16 478.0 0.23 B A F 17 391.0 0.23 B 18 463.9 0.21
C C 19 404.2 0.65 G G 20 464.1 0.26 A A E E 21 479.4 0.26 A A E E D
22 389.9 0.12 A A E F E D 23 387.9 0.11 A B E F G 24 404.8 0.25 A B
E F E E 25 376.0 0.16 A A E 26 390.1 0.17 A B F 27 457.1 0.21 B B
28 458.1 0.14 A B F 29 458.1 0.14 A A E E 30 443.9 0.11 A C 31
470.1 0.17 A A E D 32 487.1 0.58 A B 33 442.9 0.14 A A E E 34 495.9
0.12 A A E 35 540.1 0.12 A B F 36 575.9 0.21 A 37 512.1 0.51 38
506.0 0.15 A B G 39 513.2 0.13 F 40 513.1 0.11 E 41 457.2 0.18 A B
42 485.2 0.56 C B 43 472.1 0.11 C A 44 472.1 0.12 B C 45 473.1 0.12
A A F E D 46 486.1 0.10 A A F E 47 473.2 0.68 A A D E 48 487.1 0.70
A A E E 49 496.2 0.46 A A E D D D 50 459.0 0.14 A A F E 51 475.2
0.33 A A E 52 461.1 0.19 A A D D D D 53 468.1 0.20 A A E E 54 443.1
0.15 A A D E 55 461.0 0.22 A B E 56 457.1 0.14 A B E E 57 497.2
0.80 A A E F 58 506.1 0.19 A A D E 59 509.0 0.61 A A E D D E 60
511.1 1.21 A B F 61 494.1 0.40 A A D E D E 62 469.0 0.27 A B 63
513.0 0.23 A A 64 506.9 0.34 A E 65 563.2 1.58 A C F 66 499.1 1.25
A A F E 67 495.0 0.39 A A E E 68 574.0 0.63 A A D E 69 513.1 0.39 A
70 527.2 0.21 A A E E 71 523.9 0.29 A A 72 527.0 1.00 A 73 509.2
0.67 A 74 523.2 1.27 A 75 509.2 0.30 A A 76 483.0 0.50 A A D E 77
506.1 0.20 A A E 78 483.2 0.46 A 79 495.0 0.34 A 80 509.0 0.16 G 81
505.0 0.33 A A D E 82 505.0 0.14 A A D E 83 541.2 0.09 A B E 84
528.2 0.10 A A E E 85 559.2 0.11 A A E E 86 559.2 0.10 A B F 87
526.2 0.09 A C 88 513.4 0.64 B B 89 527.2 0.09 A A F 90 478.9 0.10
C C 91 493.6 0.09 C C 92 448.9 0.09 C C 93 463.5 0.10 C C 94 408.2
0.21 B C 95 487.0 0.45 A B D E E 96 480.1 0.14 A A 97 524.0 0.17 A
A E 98 469.3 0.22 A A E 99 523.9 0.38 A A E 100 485.2 0.09 A B F
101 484.2 0.10 A B E 102 500.0 0.09 A B E 103 443.0 0.14 A B D D
104 457.2 0.25 A A D E 105 471.2 0.38 A A F E 106 470.2 0.10 A B F
107 565.2 1.05 A 108 556.2 0.33 A A E 109 444.2 0.11 A B F E 110
512.2 0.09 B E 111 457.0 0.20 A B E 112 554.9 0.10 A A 113 514.2
0.11 A A F 114 541.2 0.09 A A E 115 487.0 0.42 A A E 116 542.2 0.10
A C F 117 567.3 0.10 A A E 118 485.0 0.66 A A F F F 119 461.1 0.19
A A D E D D 120 573.0 0.61 121 558.9 0.36 122 584.9 0.80 123 479.2
0.26 A B E 124 512.1 0.61 A B G 125 512.4 0.46 A A E 126 487.3 0.36
Activities (nM): A: IC.sub.50 < 50; B: IC.sub.50 = 50-200; C:
IC.sub.50 = 201-10,000; D: IC.sub.50 < 100; E: IC.sub.50 =
100-500; F: IC.sub.50 = 501-5000; G: IC.sub.50 > 1000.
[0312] All publications cited in this specification and priority
applications including U.S. Provisional Patent Application No.
61/678,694, filed Aug. 2, 2012, are incorporated herein by
reference. While the invention has been described with reference to
particular embodiments, it will be appreciated that modifications
can be made without departing from the spirit of the invention.
Such modifications are intended to fall within the scope of the
appended claims.
* * * * *